Azetidinyl diamides as monoacylglycerol lipase inhibitors

ABSTRACT

Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula (I) as follows: 
     
       
         
         
             
             
         
       
     
     wherein Y, Z, R 1 , and s are defined herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. provisional patent applicationNos. 61/171,658 and 61/171,649, each filed Apr. 22, 2009, which arehereby incorporated by reference in their entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The research and development of the invention described below was notfederally sponsored.

BACKGROUND OF THE INVENTION

Cannabis sativa has been used for the treatment of pain for many years.Δ⁹-tetrahydrocannabinol is a major active ingredient from Cannabissativa and an agonist of cannabinoid receptors (Pertwee, Brit JPharmacol, 2008, 153, 199-215). Two cannabinoid G protein-coupledreceptors have been cloned, cannabinoid receptor type 1 (CB₁ Matsuda etal., Nature, 1990, 346, 561-4) and cannabinoid receptor type 2 (CB₂Munro et al., Nature, 1993, 365, 61-5). CB₁ is expressed centrally inbrain areas, such as the hypothalamus and nucleus accumbens as well asperipherally in the liver, gastrointestinal tract, pancreas, adiposetissue, and skeletal muscle (Di Marzo et al., Curr Opin Lipidol, 2007,18, 129-140). CB₂ is predominantly expressed in immune cells, such asmonocytes (Pacher et al., Amer J Physiol, 2008, 294, H1133-H1134), andunder certain conditions, also in the brain (Benito et al., Brit JPharmacol, 2008, 153, 277-285) and in skeletal (Cavuoto et al., BiochemBiophys Res Commun, 2007, 364, 105-110) and cardiac (Hajrasouliha etal., Eur J Pharmacol, 2008, 579, 246-252) muscle. An abundance ofpharmacological, anatomical and electrophysiological data, usingsynthetic agonists, indicate that increased cannabinoid signalingthrough CB₁/CB₂ promotes analgesia in tests of acute nociception andsuppresses hyperalgesia in models of chronic neuropathic andinflammatory pain (Cravatt et al., J Neurobiol, 2004, 61, 149-60;Guindon et al., Brit J Pharmacol, 2008, 153, 319-334).

Efficacy of synthetic cannabinoid receptor agonists is well documented.Moreover, studies using cannabinoid receptor antagonists and knockoutmice have also implicated the endocannabinoid system as an importantmodulator of nociception. Anandamide (AEA) (Devane et al., Science,1992, 258, 1946-9) and 2-arachidinoylglycerol (2-AG) (Mechoulam et al.,Biochem Pharmacol, 1995, 50, 83-90; Sugiura et al., Biochem Biophys ResCommun, 1995, 215, 89-97) are 2 major endocannabinoids. AEA ishydrolyzed by fatty acid amide hydrolase (FAAH) and 2-AG is hydrolyzedby monoacylglycerol lipase (MGL) (Piomelli, Nat Rev Neurosci, 2003, 4,873-884). Genetic ablation of FAAH elevates endogenous AEA and resultsin a CB₁-dependent analgesia in models of acute and inflammatory pain(Lichtman et al., Pain, 2004, 109, 319-27), suggesting that theendocannabinoid system functions naturally to inhibit pain (Cravatt etal., J Neurobiol, 2004, 61, 149-60). Unlike the constitutive increase inendocannabinoid levels using FAAH knockout mice, use of specific FAAHinhibitors transiently elevates AEA levels and results inantinociception in vivo (Kathuria et al., Nat Med, 2003, 9, 76-81).Further evidence for an endocannabinoid-mediated antinociceptive tone isdemonstrated by the formation of AEA in the periaqueductal greyfollowing noxious stimulation in the periphery (Walker et al., Proc NatlAcad Sci USA, 1999, 96, 12198-203) and, conversely, by the induction ofhyperalgesia following antisense RNA-mediated inhibition of CB₁ in thespinal cord (Dogrul et al., Pain, 2002, 100, 203-9).

With respect to 2-AG, intravenous delivery of 2-AG produces analgesia inthe tail flick (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-90)and hot plate (Lichtman et al., J Pharmacol Exp Ther, 2002, 302, 73-9)assays. In contrast, it was demonstrated that 2-AG given alone is notanalgesic in the hot plate assay, but when combined with other2-monoacylglycerols (i.e., 2-linoleoyl glycerol and 2-palmitoylglycerol), significant analgesia is attained, a phenomenon termed the“entourage effect” (Ben-Shabat et al., Eur J Pharmacol, 1998, 353,23-31). These “entourage” 2-monoacylglycerols are endogenous lipids thatare co-released with 2-AG and potentiate endocannabinoid signaling, inpart, by inhibiting 2-AG breakdown, most likely by competition for theactive site on MGL. This suggests that synthetic MGL Inhibitors willhave a similar effect. Indeed, URB602, a relatively weak synthetic MGLInhibitor, showed an antinociceptive effect in a murine model of acuteinflammation (Comelli et al., Brit J Pharmacol, 2007, 152, 787-794).

Although the use of synthetic cannabinoid agonists have conclusivelydemonstrated that increased cannabinoid signaling produces analgesic andanti-inflammatory effects, it has been difficult to separate thesebeneficial effects from the unwanted side effects of these compounds. Analternative approach is to enhance the signaling of the endocannabinoidsystem by elevating the level of 2-AG, the endocannabinoid of highestabundance in the central nervous system (CNS) and gastrointestinaltract, which may be achieved by inhibition of MGL. Therefore, MGLInhibitors are potentially useful for the treatment of pain,inflammation, and CNS disorders (Di Marzo et al., Curr Pharm Des, 2000,6, 1361-80; Jhaveri et al., Brit J Pharmacol, 2007, 152, 624-632;McCarberg Bill et al., Amer J Ther, 2007, 14, 475-83), as well asglaucoma and disease states arising from elevated intraocular pressure(Njie, Ya Fatou; He, Fang; Qiao, Zhuanhong; Song, Zhao-Hui, Exp. EyeRes., 2008, 87(2):106-14).

SUMMARY OF THE INVENTION

The present invention is directed to a compound of Formula (I)

wherein

Y and Z are independently selected from a) or b) such that one of Y andZ is selected from group a) and the other is selected from group b);

-   -   Group a) is unsubstituted C₆₋₁₀ aryl,    -   Group b) is        -   i) C₆₋₁₀ aryl; or        -   ii) heteroaryl selected from the group consisting of            thiazolyl, pyridinyl, indolyl, indazolyl, benzoxazolyl,            benzothiazolyl, benzofuranyl, benzothienyl,            imidazo[1,2-a]pyridin-2-yl, quinolinyl, quinazolinyl,            furanyl, thienyl, oxazolyl, pyrazolyl, and benzimidazolyl;

with the proviso that a heteroaryl of Group b) is substituted with otherthan C₁₋₄-alkoxy;

wherein C₆₋₁₀ aryl and heteroaryl of Group b) are optionallyindependently substituted with one to two substitutents selected fromthe group consisting of bromo, chloro, fluoro, iodo, C₁₋₄alkyl,C₁₋₄alkoxy, and trifluoromethyl; and are substituted with one additionalsubstituent selected from the group consisting of

-   -   i) C₆₋₁₀ aryl; or    -   ii) heteroaryl selected from the group consisting of        pyrimidinyl, thienyl, quinolinyl, pyridinyl, thiazolyl,        benzimidazolyl, pyrrolyl, and pyrazolyl;

wherein phenyl of the C₆₋₁₀aryl and the heteroaryl are optionallyindependently substituted with one to two substituents selected from thegroup consisting of C₁₋₄alkoxycarbonylamino; C₁₋₄alkyl; cyanomethyl;C₁₋₄alkoxy; one to three fluoro or chloro substituents; trifluoromethyl;trifluoromethoxy; trifluoromethylthio; C₁₋₄alkylcarbonyl;C₁₋₄alkoxycarbonyl; C₁₋₄alkoxycarbonyl(C₂₋₄)alkenyl; cyano(C₂₋₄)alkenyl;(2-cyano)ethylaminocarbonyl; cyano; carboxy; aminocarbonyl;C₁₋₄alkylaminocarbonyl; di(C₁₋₄alkyl)aminocarbonyl; formyl; nitro;bromo; hydroxy; di(C₁₋₄alkyl)aminosulfonyl; C₁₋₄alkylsulfonyl;di(C₁₋₄alkyl)aminosulfonyl; morpholin-4-ylsulfonyl; —OCH₂O— attached atadjacent carbon atoms; and NR^(c)R^(d); wherein R^(c) is hydrogen orC₁₋₆alkyl and wherein Rd is hydrogen, C₁₋₆alkyl, cyano(C₁₋₄)alkyl,C₃₋₈cycloalkyl, C₁₋₆alkylcarbonyl, C₃₋₈cycloalkylcarbonyl,C₃₋₈cycloalkyl(C₁₋₄)alkyl, aminocarbonyl, di(C₁₋₄alkyl)aminocarbonyl,C₆₋₁₀arylcarbonyl; di(C₁₋₄alkyl)aminosulfonyl, and C₁₋₄alkylsulfonyl;

s is 0, 1 or 2; provided that when s is 2, R¹ is independently selectedfrom the group consisting of phenyl, C₁₋₃alkyl, andC₆₋₁₀aryl(C₁₋₃)alkyl;

R¹ is C₆₋₁₀aryl, C₁₋₃alkyl, benzyloxymethyl, hydroxy(C₁₋₃)alkyl,aminocarbonyl, carboxy, trifluoromethyl, spirofused cyclopropyl, 3-oxo,or aryl(C₁₋₃)alkyl; or, when s is 2 and R¹ is C₁₋₃alkyl, the C₁₋₃alkylsubstituents are taken with the piperizinyl ring to form a3,8-diaza-bicyclo[3.2.1]octanyl or 2,5-diaza-bicyclo[2.2.2]octanyl ringsystem;

with the proviso that when Y is phenyl, Z is other than3-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-2-yl)phenyl,2-(2-fluorophenyl)phenyl, 2-(4-fluorophenyl)phenyl,4-(3-cyanophenyl)phenyl 4-(pyrazol-1-yl)phenyl,1-ethylcarbonyl-3,4-dihydro-1H-isoquinolin-2-yl, 2-phenylethynyl,6-bromo-imidazo[1,2-α]pyridin-2-yl,

and with the proviso that a compound of Formula (I) is other than acompound wherein Y is phenyl, Z is biphenyl-4-yl, s is 1, and R¹ isspirofused cyclopropyl; and enantiomers, diastereomers, solvates, andpharmaceutically acceptable salts thereof.

The present invention also provides, inter alia, a pharmaceuticalcomposition comprising, consisting of and/or consisting essentially of apharmaceutically acceptable carrier, a pharmaceutically acceptableexcipient, and/or a pharmaceutically acceptable diluent and a compoundof Formula (I) or a pharmaceutically acceptable salt form thereof.

Also provided are processes for making a pharmaceutical compositioncomprising, consisting of, and/or consisting essentially of admixing acompound of Formula (I) and a pharmaceutically acceptable carrier, apharmaceutically acceptable excipient, and/or a pharmaceuticallyacceptable diluent.

The present invention further provides, inter alia, methods for treatingor ameliorating a MGL-modulated disorder in a subject, including a humanor other mammal in which the disease, syndrome, or condition is affectedby the modulation of MGL, such as pain and the diseases that lead tosuch pain, inflammation and CNS disorders, using a compound of Formula(I).

The present invention also provides, inter alia, methods for producingthe instant compounds and pharmaceutical compositions and medicamentsthereof.

DETAILED DESCRIPTION OF THE INVENTION

With reference to substituents, the term “independently” refers to thesitutaion that when more than one substituent is possible, thesubstituents may be the same or different from each other.

The term “alkyl” whether used alone or as part of a substituent group,refers to straight and branched carbon chains having 1 to 8 carbonatoms. Therefore, designated numbers of carbon atoms (e.g., C₁₋₈) referindependently to the number of carbon atoms in an alkyl moiety or to thealkyl portion of a larger alkyl-containing substituent. In substituentgroups with multiple alkyl groups, such as (C₁₋₆alkyl)₂-amino, theC₁₋₆alkyl groups of the dialkylamino may be the same or different.

The term “alkoxy” refers to an —O-alkyl group, wherein the term “alkyl”is as defined above.

The terms “alkenyl” and “alkynyl” refer to straight and branched carbonchains having 2 or more carbon atoms, wherein an alkenyl chain containsat least one double bond and an alkynyl chain contains at least onetriple bond.

The term “cycloalkyl” refers to saturated or partially saturated,monocyclic or polycyclic hydrocarbon rings of 3 to 14 carbon atoms.Examples of such rings include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and adamantyl.

The term “benzo-fused cycloalkyl” refers to a 5- to 8-memberedmonocyclic cycloalkyl ring fused to a benzene ring. The carbon atom ringmembers that form the cycloalkyl ring may be fully saturated orpartially saturated.

The term “heterocyclyl” refers to a nonaromatic monocyclic or bicyclicring system having 3 to 10 ring members and which contains carbon atomsand from 1 to 4 heteroatoms independently selected from the groupconsisting of N, O, and S. Included within the term heterocyclyl is anonaromatic cyclic ring of 5 to 7 members in which 1 to 2 members arenitrogen, or a nonaromatic cyclic ring of 5 to 7 members in which 0, 1or 2 members are nitrogen and up to 2 members are oxygen or sulfur andat least one member must be either nitrogen, oxygen or sulfur; wherein,optionally, the ring contains zero to one unsaturated bonds, and,optionally, when the ring is of 6 or 7 members, it contains up to 2unsaturated bonds. The carbon atom ring members that form a heterocyclering may be fully saturated or partially saturated. The term“heterocyclyl” also includes two 5 membered monocyclic heterocycloalkylgroups bridged to form a bicyclic ring. Such groups are not consideredto be fully aromatic and are not referred to as heteroaryl groups. Whena heterocycle is bicyclic, both rings of the heterocycle arenon-aromatic and at least one of the rings contains a heteroatom ringmember. Examples of heterocycle groups include, and are not limited to,pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl),pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. Unlessotherwise noted, the heterocycle is attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure.

The term “benzo-fused heterocyclyl” refers to a 5 to 7 memberedmonocyclic heterocycle ring fused to a benzene ring. The heterocyclering contains carbon atoms and from 1 to 4 heteroatoms independentlyselected from the group consisting of N, O, and S. The carbon atom ringmembers that form the heterocycle ring may be fully saturated orpartially saturated. Unless otherwise noted, benzo-fused heterocyclering is attached to its pendant group at a carbon atom of the benzenering.

The term “aryl” refers to an unsaturated, aromatic monocyclic orbicyclic ring of 6 to 10 carbon members. Examples of aryl rings includephenyl and naphthalenyl.

The term “heteroaryl” refers to an aromatic monocyclic or bicyclicaromatic ring system having 5 to 10 ring members and which containscarbon atoms and from 1 to 4 heteroatoms independently selected from thegroup consisting of N, O, and S. Included within the term heteroaryl arearomatic rings of 5 or 6 members wherein the ring consists of carbonatoms and has at least one heteroatom member. Suitable heteroatomsinclude nitrogen, oxygen, and sulfur. In the case of 5 membered rings,the heteroaryl ring preferably contains one member of nitrogen, oxygenor sulfur and, in addition, up to 3 additional nitrogens. In the case of6 membered rings, the heteroaryl ring preferably contains from 1 to 3nitrogen atoms. For the case wherein the 6 membered ring has 3nitrogens, at most 2 nitrogen atoms are adjacent. When a heteroaryl isbicyclic, at least one heteroatom is present in each ring. Examples ofheteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. Unlessotherwise noted, the heteroaryl is attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure.

Unless otherwise noted, the term “benzo fused heteroaryl” refers to a 5to 6 membered monocyclic heteroaryl ring fused to a benzene ring. Theheteroaryl ring contains carbon atoms and from 1 to 4 heteroatomsindependently selected from the group consisting of N, O, and S.Examples of heteroaryl groups with the optionally fused benzene ringsinclude indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl,indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl,benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl andquinazolinyl. Unless otherwise noted, the benzo-fused heteroaryl isattached to its pendant group at any heteroatom or carbon atom thatresults in a stable structure.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine andiodine.

-   -   The term “formyl” refers to the group —C(═O)H.    -   The term “oxo” refers to the group (═O).

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g., arylalkyl, alkylamino) the nameis to be interpreted as including those limitations given above for“alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C₁-C₆)refer independently to the number of carbon atoms in an alkyl moiety, anaryl moiety, or in the alkyl portion of a larger substituent in whichalkyl appears as its prefix root. For alkyl and alkoxy substituents, thedesignated number of carbon atoms includes all of the independentmembers included within a given range specified. For example C₁₋₆ alkylwould include methyl, ethyl, propyl, butyl, pentyl and hexylindividually as well as sub-combinations thereof (e.g., C₁₋₂, C₁₋₃,C₁₋₄, C₁₋₅, C₂₋₆, C₃₋₆, C₄₋₆, C₅₋₆, C₂₋₅, etc.).

In general, under standard nomenclature rules used throughout thisdisclosure, the terminal portion of the designated side chain isdescribed first followed by the adjacent functionality toward the pointof attachment. Thus, for example, a “C₁-C₆ alkylcarbonyl” substituentrefers to a group of the formula:

The numbering system shown below is used for describing the position ofR¹ substituents on the piperazinyl ring of Formula (I):

The term “R” at a stereocenter designates that the stereocenter ispurely of the R-configuration as defined in the art; likewise, the term“S” means that the stereocenter is purely of the S-configuration. Asused herein, the terms “*R” or “*S” at a stereocenter are used todesignate that the stereocenter is of pure but unknown configuration. Asused herein, the term “RS” refers to a stereocenter that exists as amixture of the R- and S-configurations. Similarly, the terms “*RS” or“*SR” refer to a stereocenter that exists as a mixture of the R- andS-configurations and is of unknown configuration relative to anotherstereocenter within the molecule.

Compounds containing one stereocenter drawn without a stereo bonddesignation are a mixture of 2 enantiomers. Compounds containing 2stereocenters both drawn without stereo bond designations are a mixtureof 4 diastereomers. Compounds with 2 stereocenters both labeled “RS” anddrawn with stereo bond designations are a 2-component mixture withrelative stereochemistry as drawn. Compounds with 2 stereocenters bothlabeled “*RS” and drawn with stereo bond designations are a 2-componentmixture with relative stereochemistry unknown. Unlabeled stereocentersdrawn without stereo bond designations are a mixture of the R- andS-configurations. For unlabeled stereocenters drawn with stereo bonddesignations, the absolute stereochemistry is as depicted.

Unless otherwise noted, it is intended that the definition of anysubstituent or variable at a particular location in a molecule beindependent of its definitions elsewhere in that molecule. It isunderstood that substituents and substitution patterns on the compoundsof Formula (I) as herein defined can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art as wellas those methods set forth herein.

The term “subject” refers to an animal, preferably a mammal, mostpreferably a human, who has been the object of treatment, observation orexperiment.

The term “therapeutically effective amount” refers to an amount of anactive compound or pharmaceutical agent, including a compound of thepresent invention, which elicits the biological or medicinal response ina tissue system, animal or human that is being sought by a researcher,veterinarian, medical doctor or other clinician, which includesalleviation or partial alleviation of the symptoms of the disease,syndrome, condition, or disorder being treated.

The term “composition” refers to a product that includes the specifiedingredients in therapeutically effective amounts, as well as any productthat results, directly, or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “MGL inhibitor” is intended to encompass a compound thatinteracts with MGL to substantially reduce or eliminate its catalyticactivity, thereby increasing the concentrations of its substrate(s). Theterm “MGL-modulated” is used to refer to the condition of being affectedby the modulation of the MGL enzyme including the condition of beingaffected by the inhibition of the MGL enzyme, such as, for example, painand the diseases that lead to such pain, inflammation and CNS disorders.

As used herein, unless otherwise noted, the term “affect” or “affected”(when referring to a disease, syndrome, condition or disorder that isaffected by inhibition of MGL) shall include a reduction in thefrequency and/or severity of one or more symptoms or manifestations ofsaid disease, syndrome, condition or disorder; and/or include theprevention of the development of one or more symptoms or manifestationsof said disease, syndrome, condition or disorder or the development ofthe disease, condition, syndrome or disorder.

The compounds of Formula (I) are useful in methods for treating,ameliorating and/or preventing a disease, a syndrome, a condition or adisorder that is affected by the inhibition of MGL. Such methodscomprise, consist of and/or consist essentially of administering to asubject, including an animal, a mammal, and a human in need of suchtreatment, amelioration and/or prevention, a therapeutically effectiveamount of a compound of Formula (I) as herein defined, or an enantiomer,diastereomer, solvate or pharmaceutically acceptable salt thereof. Inparticular, the compounds of Formula (I) as herein defined are usefulfor treating, ameliorating and/or preventing pain; diseases, syndromes,conditions, or disorders causing such pain; inflammation and/or CNSdisorders. More particularly, the compounds of Formula (I) as hereindefined are useful for treating, ameliorating and/or preventinginflammatory pain, inflammatory hypersensitivity conditions and/orneuropathic pain, comprising administering to a subject in need thereofa therapeutically effective amount of a compound of Formula (I), asherein defined.

Examples of inflammatory pain include pain due to a disease, condition,syndrome, disorder, or a pain state including inflammatory boweldisease, visceral pain, migraine, post operative pain, osteoarthritis,rheumatoid arthritis, back pain, lower back pain, joint pain, abdominalpain, chest pain, labor, musculoskeletal diseases, skin diseases,toothache, pyresis, burn, sunburn, snake bite, venomous snake bite,spider bite, insect sting, neurogenic bladder, interstitial cystitis,urinary tract infection, rhinitis, contact dermatitis/hypersensitivity,itch, eczema, pharyngitis, mucositis, enteritis, irritable bowelsyndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome,menstrual pain, endometriosis, pain due to physical trauma, headache,sinus headache, tension headache, or arachnoiditis.

One type of inflammatory pain is inflammatoryhyperalgesia/hypersensitivity. Examples of inflammatory hyperalgesiainclude a disease, syndrome, condition, disorder, or pain stateincluding inflammation, osteoarthritis, rheumatoid arthritis, back pain,joint pain, abdominal pain, musculoskeletal diseases, skin diseases,post operative pain, headaches, toothache, burn, sunburn, insect sting,neurogenic bladder, urinary incontinence, interstitial cystitis, urinarytract infection, cough, asthma, chronic obstructive pulmonary disease,rhinitis, contact dermatitis/hypersensitivity, itch, eczema,pharyngitis, enteritis, irritable bowel syndrome, inflammatory boweldiseases including Crohn's Disease, ulcerative colitis, urinaryincontinence, benign prostatic hypertrophy, cough, asthma, rhinitis,nasal hypersensitivity, itch, contact dermintisi and/or dermal allergyand chronic obstructive pulmonary disease.

In an embodiment, the present invention is directed to a method fortreating, ameliorating and/or preventing inflammatory visceralhyperalgesia in which a enhanced visceral irritability exists,comprising, consisting of, and/or consisting essentially of the step ofadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound, salt or solvate of Formula (I), asherein defined. In a further embodiment, the present invention isdirected to a method for treating inflammatory somatic hyperalgesia inwhich a hypersensitivity to thermal, mechanical and/or chemical stimuliexists, comprising administering to a mammal in need of such treatment atherapeutically effective amount of a compound of formula (I) or anenantiomer, diastereomer, solvate or pharmaceutically acceptable saltthereof

A further embodiment of the present invention is directed to a methodfor treating, ameliorating and/or preventing neuropathic pain. Examplesof a neuropathic pain include pain due to a disease, syndrome,condition, disorder, or pain state including cancer, neurologicaldisorders, spine and peripheral nerve surgery, brain tumor, traumaticbrain injury (TBI), spinal cord trauma, chronic pain syndrome,fibromyalgia, chronic fatigue syndrome, lupus, sarcoidosis, peripheralneuropathy, bilateral peripheral neuropathy, diabetic neuropathy,central pain, neuropathies associated with spinal cord injury, stroke,amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiplesclerosis, sciatic neuritis, mandibular joint neuralgia, peripheralneuritis, polyneuritis, stump pain, phantom limb pain, bony fractures,oral neuropathic pain, Charcot's pain, complex regional pain syndrome Iand II (CRPS I/II), radiculopathy, Guillain-Barre syndrome, meralgiaparesthetica, burning-mouth syndrome, optic neuritis, postfebrileneuritis, migrating neuritis, segmental neuritis, Gombault's neuritis,neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculateneuralgia, glossopharyngial neuralgia, migrainous neuralgia, idiopathicneuralgia, intercostals neuralgia, mammary neuralgia, Morton'sneuralgia, nasociliary neuralgia, occipital neuralgia, postherpeticneuralgia, causalgia, red neuralgia, Sluder's neuralgia, splenopalatineneuralgia, supraorbital neuralgia, trigeminal neuralgia, vulvodynia, orvidian neuralgia.

One type of neuropathic pain is neuropathic cold allodynia, which can becharacterized by the presence of a neuropathy-associated allodynic statein which a hypersensitivity to cooling stimuli exists. Examples ofneuropathic cold allodynia include allodynia due to a disease,condition, syndrome, disorder or pain state including neuropathic pain(neuralgia), pain arising from spine and peripheral nerve surgery ortrauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpeticneuralgia, causalgia, peripheral neuropathy, diabetic neuropathy,central pain, stroke, peripheral neuritis, polyneuritis, complexregional pain syndrome I and II (CRPS I/II) and radiculopathy.

In a further embodiment, the present invention is directed to a methodfor treating, ameliorating and/or preventing neuropathic cold allodyniain which a hypersensitivity to a cooling stimuli exists, comprising,consisting of, and/or consisting essentially of the step ofadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of Formula (I), as herein defined, or anenantiomer, diastereomer, solvate or pharmaceutically acceptable saltthereof.

In a further embodiment, the present invention is directed to a methodfor treating, ameliorating and/or preventing CNS disorders. Examples ofCNS disorders include anxieties, such as social anxiety, post-traumaticstress disorder, phobias, social phobia, special phobias, panicdisorder, obsessive-compulsive disorder, acute stress, disorder,separation anxiety disorder, and generalized anxiety disorder, as wellas depression, such as major depression, bipolar disorder, seasonalaffective disorder, post natal depression, manic depression, and bipolardepression.

The present invention includes a pharmaceutical composition comprising acompound of Formula (I) wherein:

wherein

a) Group b) is

-   -   i) C₆₋₁₀ aryl; or    -   ii) heteroaryl selected from the group consisting of thiazolyl,        pyridinyl, indolyl, indazolyl, benzoxazolyl, benzothiazolyl,        benzofuranyl, benzothienyl, quinolinyl, quinazolinyl, thienyl,        furanyl, and benzimidazolyl;        -   wherein C₆₋₁₀ aryl and heteroaryl of Group b) are optionally            independently substituted with one to two substituents            independently selected from the group consisting of bromo,            chloro, fluoro, iodo, methyl, methoxy, and trifluoromethyl,            and are substituted with one additional substituent selected            from the group consisting of    -   i) C₆₋₁₀ aryl; and    -   ii) heteroaryl selected from the group consisting of thienyl,        quinolinyl, pyridinyl, pyrazolyl, and benzimidazolyl, and        pyrrolyl;        -   wherein phenyl of the C₆₋₁₀aryl, and the heteroaryl            substituent are optionally independently substituted with            one to two substituents selected from the group consisting            of C₁₋₄alkoxycarbonylamino; C₁₋₄alkoxycarbonyl; C₁₋₄alkyl;            cyanomethyl; C₁₋₄alkoxy; one to three fluoro or chloro            substituents; trifluoromethyl; trifluoromethoxy;            C₁₋₄alkylcarbonyl; C₁₋₄alkoxycarbonyl(C₂₋₄)alkenyl;            cyano(C₂₋₄)alkenyl; (2-cyano)ethylaminocarbonyl; cyano;            carboxy; aminocarbonyl; di(C₁₋₄alkyl)aminocarbonyl; formyl;            nitro; bromo; hydroxy; di(C₁₋₄alkyl)aminosulfonyl;            C₁₋₄alkylsulfonyl; morpholin-4-ylsulfonyl; and NR^(c)R^(d)            wherein R^(c) is hydrogen or C₁₋₆alkyl and wherein R^(d) is            hydrogen, C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆alkylcarbonyl,            di(C₁₋₄alkyl)aminosulfonyl, and C₁₋₄alkylsulfonyl;

b) Group b) is

-   -   i) C₆₋₁₀ aryl; or    -   ii) heteroaryl selected from the group consisting of thiazolyl,        pyridinyl, indolyl, indazolyl, benzoxazolyl, benzothiazolyl,        benzothienyl, quinolinyl, quinazolinyl, thienyl, and        benzimidazolyl;        -   wherein C₆₋₁₀ aryl and heteroaryl of Group b) are optionally            independently substituted with one to two substituents            independently selected from the group consisting of bromo,            chloro, fluoro, iodo, methyl, methoxy, and trifluoromethyl,            and are substituted with one additional substituent selected            from the group consisting of    -   i) C₆₋₁₀ aryl; and    -   ii) heteroaryl selected from the group consisting of        pyrimidinyl, thienyl, quinolinyl, pyridinyl, benzimidazolyl, and        pyrrolyl;        -   wherein phenyl of the C₆₋₁₀aryl, and the heteroaryl            substituent are optionally independently substituted with            one to two substituents selected from the group consisting            of C₁₋₄alkoxycarbonylamino; C₁₋₄alkoxycarbonyl; C₁₋₄alkyl;            cyanomethyl; C₁₋₄alkoxy; one to three fluoro or chloro            substituents; _(tri)fluoromethyl; trifluoromethoxy;            C₁₋₄alkylcarbonyl; C₁₋₄alkoxycarbonyl(C₂₋₄)alkenyl;            cyano(C₂₋₄)alkenyl; (2-cyano)ethylaminocarbonyl; cyano;            carboxy; aminocarbonyl; di(C₁₋₄alkyl)aminocarbonyl; formyl;            nitro; bromo; hydroxy; di(C₁₋₄alkyl)aminosulfonyl;            C₁₋₄alkylsulfonyl; morpholin-4-ylsulfonyl, _(a)nd            NR^(c)R^(d) wherein R^(c) is hydrogen or C₁₋₆alkyl and            wherein _(Rd) is hydrogen, C₁₋₆alky_(l), C₃₋₈cycloalkyl,            C₁₋₆alkylcarbonyl, di(C₁₋₄alk^(y)l)aminosulfo^(n)yl, and            C₁₋₄alkyl_(sul)fonyl;

c) Group b is

-   -   i) C₆₋₁₀ aryl;    -   ii) heteroaryl selected from the group consisting of indolyl,        indazolyl, benzoxazolyl, benzothienyl, and thienyl;        -   wherein C₆₋₁₀ aryl and heteroaryl of Group b) are optionally            independently substituted with one to two substituents            independently selected from the group consisting of bromo,            chloro, fluoro, iodo, methyl, methoxy, and trifluoromethyl,            and are substituted with one additional substituent selected            from the group consisting of    -   i) C₆₋₁₀ aryl; and    -   ii) heteroaryl selected from the group consisting of        pyrimidinyl, thienyl, and quinolinyl;        -   wherein phenyl of the C₆₋₁₀aryl and the heteroaryl            substituent are optionally independently substituted with            one to two substituents selected from the group consisting            of C₁₋₄alkoxycarbonylamino; C₁₋₄alkoxycarbonyl; C₁₋₄alkyl;            cyanomethyl; C₁₋₄alkoxy; one to three fluoro or chloro            substituents; trifluoromethyl; trifluoromethoxy;            C₁₋₄alkylcarbonyl; C₁₋₄alkoxycarbonyl(C₂₋₄)alkenyl;            cyano(C₂₋₄)alkenyl; cyano; carboxy; aminocarbonyl;            di(C₁₋₄alkyl)aminocarbonyl; formyl; nitro; bromo; hydroxy;            di(C₁₋₄alkyl)aminosulfonyl; C₁₋₄alkylsulfonyl;            morpholin-4-ylsulfonyl; and NR^(c)R^(d) wherein R^(c) is            hydrogen or C₁₋₆alkyl and wherein Rd is hydrogen, C₁₋₆alkyl,            C₃₋₈cycloalkyl, C₁₋₆alkylcarbonyl,            di(C₁₋₄alkyl)aminosulfonyl, and C₁₋₄alkylsulfonyl;            d) s is 0 or 1;            e) s is 0;            f) R¹ is phenyl, spirofused cyclopropyl, or C₁₋₃alkyl;            g) R¹ is phenyl;

and any combination of embodiments a) through g) above, provided that itis understood that combinations in which different embodiments of thesame substituent would be combined are excluded;

with the proviso that when Y is phenyl, Z is other than3-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-2-yl)phenyl,2-(2-fluorophenyl)phenyl, 2-(4-fluorophenyl)phenyl,4-(3-cyanophenyl)phenyl 4-(pyrazol-1-yl)phenyl,1-ethylcarbonyl-3,4-dihydro-1H-isoquinolin-2-yl, 2-phenylethynyl,6-bromo-imidazo[1,2-c]pyridin-2-yl,

and enantiomers, diastereomers, solvates, and pharmaceuticallyacceptable salts thereof.

An embodiment of the present invention is directed to compounds ofFormula (I)

wherein

Y and Z are independently selected from a) or b) such that one of Y andZ is selected from group a) and the other is selected from group b);

Group a) is unsubstituted C₆₋₁₀ aryl;

Group b) is

-   -   i) C₆₋₁₀ aryl; or    -   ii) heteroaryl selected from the group consisting of thiazolyl,        pyridinyl, indolyl, indazolyl, benzoxazolyl, benzothiazolyl,        benzofuranyl, benzothienyl, quinolinyl, quinazolinyl, thienyl,        furanyl, and benzimidazolyl;        -   wherein C₆₋₁₀ aryl and heteroaryl of Group b) are optionally            independently substituted with one to two substituents            independently selected from the group consisting of bromo,            chloro, fluoro, iodo, methyl, methoxy, and trifluoromethyl,            and are substituted with one additional substituent selected            from the group consisting of    -   i) C₆₋₁₀ aryl; and    -   ii) heteroaryl selected from the group consisting of thienyl,        quinolinyl, pyridinyl, pyrazolyl, and benzimidazolyl, and        pyrrolyl; and        -   wherein phenyl of the C₆₋₁₀aryl, and the heteroaryl            substituent are optionally independently substituted with            one to two substituents selected from the group consisting            of C₁₋₄alkoxycarbonylamino; C₁₋₄alkoxycarbonyl; C₁₋₄alkyl;            cyanomethyl; C₁₋₄alkoxy; one to three fluoro or chloro            substituents; trifluoromethyl; trifluoromethoxy;            C₁₋₄alkylcarbonyl; C₁₋₄alkoxycarbonyl(C₂₋₄)alkenyl;            cyano(C₂₋₄)alkenyl; (2-cyano)ethylaminocarbonyl; cyano;            carboxy; aminocarbonyl; di(C₁₋₄alkyl)aminocarbonyl; formyl;            nitro; bromo; hydroxy; di(C₁₋₄alkyl)aminosulfonyl;            C₁₋₄alkylsulfonyl; morpholin-4-ylsulfonyl; and NR^(c)R^(d)            wherein R^(c) is hydrogen or C₁₋₆alkyl and wherein Rd is            hydrogen, C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆alkylcarbonyl,            di(C₁₋₄alkyl)aminosulfonyl, and C₁₋₄alkylsulfonyl;

s is 0 or 1;

R¹ is phenyl, spirofused cyclopropyl, or C₁₋₃alkyl;

with the proviso that when Y is phenyl, Z is other than,3-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-2-yl)phenyl,2-(2-fluorophenyl)phenyl, 2-(4-fluorophenyl)phenyl,4-(3-cyanophenyl)phenyl 4-(pyrazol-1-yl)phenyl,1-ethylcarbonyl-3,4-dihydro-1H-isoquinolin-2-yl, 2-phenylethynyl,6-bromo-imidazo[1,2-α]pyridin-2-yl,

and enantiomers, diastereomers, solvates, and pharmaceuticallyacceptable salts thereof.

An embodiment of the present invention is directed to compounds ofFormula (I)

wherein

Y and Z are independently selected from a) or b) such that one of Y andZ is selected from group a) and the other is selected from group b);

Group a) is unsubstituted C₆₋₁₀ aryl;

Group b) is

-   -   i) C₆₋₁₀ aryl;    -   ii) heteroaryl selected from the group consisting of thiazolyl,        pyridinyl, indolyl, indazolyl, benzoxazolyl, benzothiazolyl,        benzothienyl, quinolinyl, quinazolinyl, thienyl, and        benzimidazolyl;        -   wherein C₆₋₁₀ aryl and heteroaryl of Group b) are optionally            independently substituted with one to two substituents            independently selected from the group consisting of bromo,            chloro, fluoro, iodo, methyl, methoxy, and trifluoromethyl,            and are substituted with one additional substituent selected            from the group consisting of    -   i) C₆₋₁₀ aryl; and    -   ii) heteroaryl selected from the group consisting of        pyrimidinyl, thienyl, quinolinyl, pyridinyl, benzimidazolyl, and        pyrrolyl; and        -   wherein phenyl of the C₆₋₁₀aryl, and the heteroaryl            substituent are optionally independently substituted with            one to two substituents selected from the group consisting            of C₁₋₄alkoxycarbonylamino; C₁₋₄alkoxycarbonyl; C₁₋₄alkyl;            cyanomethyl; C₁₋₄alkoxy; one to three fluoro or chloro            substituents; trifluoromethyl; trifluoromethoxy;            C₁₋₄alkylcarbonyl; C₁₋₄alkoxycarbonyl(C₂₋₄)alkenyl;            cyano(C₂₋₄)alkenyl; (2-cyano)ethylaminocarbonyl; cyano;            carboxy; aminocarbonyl; di(C₁₋₄alkyl)aminocarbonyl; formyl;            nitro; bromo; hydroxy; di(C₁₋₄alkyl)aminosulfonyl;            C₁₋₄alkylsulfonyl; morpholin-4-ylsulfonyl; and NR^(c)R^(d)            wherein R^(c) is hydrogen or C₁₋₆alkyl and wherein Rd is            hydrogen, C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆alkylcarbonyl,            di(C₁₋₄alkyl)aminosulfonyl, and C₁₋₄alkylsulfonyl;    -   s is 0 or 1;    -   R¹ is phenyl;

with the proviso that when Y is phenyl, Z is other than,3-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-2-yl)phenyl,2-(2-fluorophenyl)phenyl, 2-(4-fluorophenyl)phenyl,4-(3-cyanophenyl)phenyl 4-(pyrazol-1-yl)phenyl,1-ethylcarbonyl-3,4-dihydro-1H-isoquinolin-2-yl, 2-phenylethynyl,6-bromo-imidazo[1,2-α]pyridin-2-yl,

and enantiomers, diastereomers, solvates, and pharmaceuticallyacceptable salts thereof.

An embodiment of the present invention is directed to compounds ofFormula (I)

wherein

Y and Z are independently selected from a) or b) such that one of Y andZ is selected from group a) and the other is selected from group b);

Group a) is unsubstituted phenyl;

Group b) is

-   -   i) C₆₋₁₀ aryl; or    -   ii) heteroaryl selected from the group consisting of indolyl,        indazolyl, benzoxazolyl, benzothienyl, and thienyl;        -   wherein C₆₋₁₀ aryl and heteroaryl of Group b) are optionally            independently substituted with one to two substituents            independently selected from the group consisting of bromo,            chloro, fluoro, iodo, methyl, methoxy, and trifluoromethyl,            and are substituted with one additional substituent selected            from the group consisting of    -   i) C₆₋₁₀ aryl; and    -   ii) heteroaryl selected from the group consisting of        pyrimidinyl, thienyl, and quinolinyl;        -   wherein phenyl of the C₆₋₁₀aryl and the heteroaryl            substituent are optionally independently substituted with            one to two substituents selected from the group consisting            of C₁₋₄alkoxycarbonylamino; C₁₋₄alkoxycarbonyl; C₁₋₄alkyl;            cyanomethyl; C₁₋₄alkoxy; one to three fluoro or chloro            substituents; trifluoromethyl; trifluoromethoxy;            C₁₋₄alkylcarbonyl; C₁₋₄alkoxycarbonyl(C₂₋₄)alkenyl;            cyano(C₂₋₄)alkenyl; cyano; carboxy; aminocarbonyl;            di(C₁₋₄alkyl)aminocarbonyl; formyl; nitro; bromo; hydroxy;            di(C₁₋₄alkyl)aminosulfonyl; C₁₋₄alkylsulfonyl;            morpholin-4-ylsulfonyl; and NR^(c)R^(d) wherein R^(c) is            hydrogen or C₁₋₆alkyl and wherein Rd is hydrogen, C₁₋₆alkyl,            C₃₋₈cycloalkyl, C₁₋₆alkylcarbonyl,            di(C₁₋₄alkyl)aminosulfonyl, and C₁₋₄-alkylsulfonyl;    -   s 0 or 1;    -   R¹ is phenyl;

with the proviso that when Y is phenyl, Z is other than,3-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-2-yl)phenyl,2-(2-fluorophenyl)phenyl, 2-(4-fluorophenyl)phenyl,4-(3-cyanophenyl)phenyl 4-(pyrazol-1-yl)phenyl,1-ethylcarbonyl-3,4-dihydro-1H-isoquinolin-2-yl, 2-phenylethynyl,6-bromo-imidazo[1,2-α]pyridin-2-yl,

and enantiomers, diastereomers, solvates, and pharmaceuticallyacceptable salts thereof.

An embodiment of the present invention is directed to compounds ofFormula (I)

wherein

Y and Z are independently selected from a) or b) such that one of Y andZ is selected from group a) and the other is selected from group b);

Group a) is unsubstituted phenyl; or

Group b) is

-   -   i) C₆₋₁₀ aryl; or    -   ii) heteroaryl selected from the group consisting of indolyl,        indazolyl, benzoxazolyl, benzothienyl, and thienyl;        -   wherein C₆₋₁₀ aryl and heteroaryl of Group b) are optionally            independently substituted with one to two substituents            independently selected from the group consisting of bromo,            chloro, fluoro, iodo, methyl, methoxy, and trifluoromethyl,            and are substituted with one additional substituent selected            from the group consisting of    -   i) C₆₋₁₀ aryl; and    -   ii) heteroaryl selected from the group consisting of        pyrimidinyl, thienyl, and quinolinyl;        -   wherein phenyl of the C₆₋₁₀aryl and the heteroaryl            substituent are optionally independently substituted with            one to two substituents selected from the group consisting            of C₁₋₄alkoxycarbonylamino; C₁₋₄alkoxycarbonyl; C₁₋₄alkyl;            cyanomethyl; C₁₋₄alkoxy; one to three fluoro or chloro            substituents; trifluoromethyl; trifluoromethoxy;            C₁₋₄alkylcarbonyl; C₁₋₄alkoxycarbonyl(C₂₋₄)alkenyl;            cyano(C₂₋₄)alkenyl; cyano; carboxy; aminocarbonyl;            di(C₁₋₄alkyl)aminocarbonyl; formyl; nitro; bromo; hydroxy;            di(C₁₋₄alkyl)aminosulfonyl; C₁₋₄alkylsulfonyl;            morpholin-4-ylsulfonyl; and NR^(c)R^(d) wherein R^(c) is            hydrogen or C₁₋₆alkyl and wherein Rd is hydrogen, C₁₋₆alkyl,            C₃₋₈cycloalkyl, C₁₋₆alkylcarbonyl,            di(C₁₋₄alkyl)aminosulfonyl, and C₁₋₄alkylsulfonyl;    -   s is 0;

with the proviso that when Y is phenyl, Z is other than,3-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-2-yl)phenyl,2-(2-fluorophenyl)phenyl, 2-(4-fluorophenyl)phenyl,4-(3-cyanophenyl)phenyl 4-(pyrazol-1-yl)phenyl,1-ethylcarbonyl-3,4-dihydro-1H-isoquinolin-2-yl, 2-phenylethynyl,6-bromo-imidazo[1,2-α]pyridin-2-yl, and enantiomers, diastereomers,solvates, and pharmaceutically acceptable salts thereof.

A further embodiment of the present invention is directed to a compoundof Formula (I)

selected from the group consisting of:

-   a compound wherein Y is phenyl, Z is 4-biphenyl, and s is 0;-   a compound wherein Y is phenyl, Z is 4-pyrrol-1-ylphenyl, and s is    0;-   a compound wherein Y is phenyl, Z is 4-(4-fluorophenyl)phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is 4-(4-methoxyphenyl)phenyl, and    s is 0;-   a compound wherein Y is phenyl, Z is 4-(2-chlorophenyl)phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is 4-(3,4-dichlorophenyl)phenyl,    and s is 0;-   a compound wherein Y is 4-biphenyl, Z is phenyl, and s is 1, and R¹    is 3-phenyl;-   a compound wherein Y is phenyl, Z is 2-phenylbenzoxazol-6-yl, and s    is 0;-   a compound wherein Y is phenyl, Z is 6-phenyl-naphth-2-yl, and s is    0;-   a compound wherein Y is phenyl, Z is 7-phenyl-quinolin-3-yl, and s    is 0;-   a compound wherein Y is phenyl, Z is    2-(4-methoxyphenyl)benzoxazol-6-yl, and s is 0;-   a compound wherein Y is phenyl, Z is 5-phenylthien-2-yl, and s is 0;-   a compound wherein Y is phenyl, Z is 4-methyl-2-phenylthiazol-5-yl,    and s is 0;-   a compound wherein Y is phenyl, Z is    4-methyl-2-thien-2-yl-thiazol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    4-methyl-2-(4-methylphenyl)-thiazol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    4-methyl-2-(4-trifluoromethylphenyl)-thiazol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    6-(4-trifluoromethylphenyl)benzothien-2-yl, and s is 0;-   a compound wherein Y is phenyl, Z is 6-phenyl-benzothien-2-yl, and s    is 0;-   a compound wherein Y is phenyl, Z is 4-(2,4-dimethoxyphenyl)phenyl,    and s is 0;-   a compound wherein Y is phenyl, Z is    4-(3-trifluoromethylphenyl)phenyl, and s is 0;-   a compound wherein Y is penta-deuterated phenyl, Z is    4-(3-trifluoromethylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is 4-(2-fluorophenyl)phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is 4-(3-isopropyloxyphenyl)phenyl,    and s is 0;-   a compound wherein Y is phenyl, Z is    4-(4-trifluoromethoxyphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is 4-(2-fluoropyridin-4-yl)phenyl,    and s is 0;-   a compound wherein Y is phenyl, Z is    4-(3-fluoro-4-methoxyphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    4-(4-methoxycarbonylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    4-(3,4,5-trifluorophenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    4-(3-diethylaminocarbonylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is 4-(3-fluorophenyl)phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is    4-(2-trifluoromethoxyphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is 4-(4-methylphenyl)phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is 4-(2-isopropyloxyphenyl)phenyl,    and s is 0;-   a compound wherein Y is phenyl, Z is    4-(2-methoxycarbonylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    4-(4-fluoro-2-methoxyphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is 4-(2,3-dimethoxyphenyl)phenyl,    and s is 0;-   a compound wherein Y is phenyl, Z is 4-(2,5-difluorophenyl)phenyl,    and s is 0;-   a compound wherein Y is phenyl, Z is    4-(2-fluoro-6-methoxyphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is 4-(2,3-difluorophenyl)phenyl,    and s is 0;-   a compound wherein Y is phenyl, Z is    4-(3-dimethylaminosulfonylamino-phenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-(4-trifluoromethylphenyl)-1H-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is 3-(thien-2-yl)phenyl, and s is    0;-   a compound wherein Y is phenyl, Z is 4-(thien-2-yl)phenyl, and s is    0;-   a compound wherein Y is phenyl, Z is 3-(pyridin-2-yl)phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is 3-(pyridin-3-yl)phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is 3-(pyridin-4-yl)phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is 4-(pyridin-3-yl)phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is    4-(2-trifluoromethylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    3-(2-trifluoromethylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    3-(4-trifluoromethylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    4-(4-trifluoromethylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    2-(4-chlorophenyl)-3H-benzimidazol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    4-(3-methanesulfonylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    4-(4-chloro-3-trifluoromethylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is 4-(3-cyanophenyl)phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is 4-(3-chlorophenyl)phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is 4-(4-chlorophenyl)phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is 4-(3,5-dichlorophenyl)phenyl,    and s is 0;-   a compound wherein Y is phenyl, Z is    4-(3-methylcarbonylamino-phenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is 1-phenyl-indol-5-yl, and s is    0;-   a compound wherein Y is phenyl, Z is    1-(3-trifluoromethylphenyl)indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    2-(3-trifluoromethylphenyl)benzoxazol-6-yl, and s is 0;-   a compound wherein Y is phenyl, Z is 4-(benzimidazol-1-yl)phenyl,    and s is 0;-   a compound wherein Y is phenyl, Z is    2-methyl-4-(3-trifluoromethylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    3-methyl-4-(3-trifluoromethylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    2-fluoro-4-(3-trifluoromethylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    3-methoxy-4-(3-trifluoromethylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    2-chloro-4-(3-trifluoromethylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is 2-phenyl-benzoxazol-5-yl, and s    is 0;-   a compound wherein Y is phenyl, Z is    2-methyl-4-(3-chloro-4-fluorophenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    2-methyl-4-(4-chloro-3-trifluoromethylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    3-methyl-4-(3-chloro-4-fluorophenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    3-methyl-4-(4-chloro-3-trifluoromethylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    3-methoxy-4-(3-chloro-4-fluorophenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    3-methoxy-4-(4-chloro-3-trifluoromethylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    2-chloro-4-(3-chloro-4-fluorophenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is    2-chloro-4-(4-chloro-3-trifluoromethylphenyl)phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is 5-phenyl-pyridin-3-yl, and s is    0;-   a compound wherein Y is phenyl, Z is 3-fluoro-4-phenyl-phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is 4-(4-cyanophenyl)phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is 4-(4-bromophenyl)phenyl, and s    is 0;-   a compound wherein Y is phenyl, 3-chloro-6-phenyl-benzothien-2-yl,    and s is 0;-   a compound wherein Y is phenyl,    5-(4-trifluoromethyl-phenyl)-thien-2-yl, and s is 0;-   a compound wherein Y is phenyl, and Z is biphenyl-4-yl, s is 1, and    R¹ is 2(R,S)-hydroxymethyl;-   a compound wherein Y is phenyl, and Z is biphenyl-4-yl, s is 1, and    R¹ is 3(R,S)-hydroxymethyl;-   a compound wherein Y is phenyl, Z is    1-(4-cyano-3-methylphenyl)-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is 1-(4-fluorophenyl)-indol-5-yl,    and s is 0;-   a compound wherein Y is penta-deuterated phenyl, Z is    1-(4-fluorophenyl)-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-(4-chloro-3-fluorophenyl)-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-(3,4,5-trifluorophenyl)-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    3-methyl-5-phenyl-benzo[b]thien-2-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-(3,4-difluorophenyl)-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    3-(3-trifluoromethylphenyl)-1H-indol-6-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-(4-trifluoromethoxyphenyl)-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-(4-fluorophenyl)-3-fluoro-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-(4-trifluoromethylphenyl)-indazol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-(3-trifluoromethoxyphenyl)-indazol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is 1-phenyl-3-methyl-indol-5-yl,    and s is 0;-   a compound wherein Y is phenyl, Z is    1-(2,5-difluorophenyl)-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-(2,4-difluorophenyl)-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-(3,5-difluorophenyl)-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    4-(5-trifluoromethyl-thien-2-yl)-phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is 1-(4-cyanophenyl)-indol-5-yl,    and s is 0;-   a compound wherein Y is phenyl, Z is    1-(3-fluorophenyl)-3-methyl-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-(4-fluorophenyl)-3-methyl-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is 1-methyl-3-phenyl-indol-6-yl,    and s is 0;-   a compound wherein Y is phenyl, Z is    1-(5-trifluoromethylpyridin-2-yl)-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is 1-phenyl-1H-indazol-5-yl, and s    is 0;-   a compound wherein Y is phenyl, Z is 1-(2-cyanophenyl)-indol-5-yl,    and s is 0;-   a compound wherein Y is phenyl, Z is 1-phenyl-3-fluoro-indol-5-yl,    and s is 0;-   a compound wherein Y is phenyl, Z is    1-(3,4-difluorophenyl)-indazol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    3-phenyl-6-trifluoromethyl-benzothien-2-yl, and s is 0;-   a compound wherein Y is phenyl, Z is 2-phenyl-benzothiazol-6-yl, and    s is 0;-   a compound wherein Y is phenyl, Z is    1-methyl-3-(3-trifluoromethylphenyl)-indol-6-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-(3-aminocarbonylphenyl)-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is 1-(pyrimidin-2-yl)-indol-5-yl,    and s is 0;-   a compound wherein Y is phenyl, Z is    1-(5-fluoropyridin-2-yl)-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    4-(4-trifluoromethylphenyl)-quinazolin-7-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-(5-fluoropyrimidin-2-yl)-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    2-(3-fluorophenyl)-1H-benzimidazol-6-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    7-(3-fluorophenyl)-1H-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is 2-phenyl-1H-benzimidazol-4-yl,    and s is 0;-   a compound wherein Y is phenyl, Z is    2-(4-fluorophenyl)-1H-benzimidazol-4-yl, and s is 0;-   a compound wherein Y is phenyl, Z is 1-(pyridin-4-yl)-indol-5-yl,    and s is 0;-   a compound wherein Y is phenyl, Z is 4-phenyl-quinazolin-7-yl, and s    is 0;-   a compound wherein Y is phenyl, Z is 5-phenyl-benzofuran-2-yl, and s    is 0;-   a compound wherein Y is 4-biphenyl, Z is phenyl, s is 1, and R1 is    spirofused 2-cyclopropyl-   a compound wherein Y is phenyl, Z is    2-(4-chlorophenyl)-1H-benzimidazol-4-yl,-   a compound wherein Y is phenyl, Z is    2-(2-chlorophenyl)-1H-benzimidazol-4-yl,-   a compound wherein Y is phenyl, Z is    2-(3-fluorophenyl)-1H-benzimidazol-4-yl, and s is 0;-   a compound wherein Y is 4-(benzimidazol-1-yl)-phenyl, Z is phenyl,    and s is 0;-   a compound wherein Y is 2-phenyl-1H-benzimidazol-5-yl, Z is phenyl,    and s is 0;-   a compound wherein Y is phenyl, Z is 2-chloro-4-phenyl-phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is 3-methyl-4-phenyl-phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is 2-fluoro-4-phenyl-phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is 3-methoxy-4-phenyl-phenyl, and    s is 0;-   a compound wherein Y is phenyl, Z is 2-methyl-4-phenyl-phenyl, and s    is 0;-   a compound wherein Y is phenyl, Z is    1-(4-fluorophenyl)-indazol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    4-methyl-2-(3-trifluoromethylphenyl)-thiazol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    4-methyl-2-(4-chlorophenyl)-thiazol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    4-methyl-2-(3-chlorophenyl)-thiazol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    4-methyl-2-(4-fluorophenyl)-thiazol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    4-(3-trifluoromethylpyrazol-1-yl)-phenyl, and s is 0;-   a compound wherein Y is phenyl, Z is 2-methyl-5-phenyl-furan-3-yl,    and s is 0;-   a compound wherein Y is phenyl, Z is    2-trifluoromethyl-5-phenyl-furan-3-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    2-phenyl-5-trifluoromethyl-oxazol-4-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-phenyl-5-trifluoromethyl-pyrazol-4-yl, and s is 0;-   a compound wherein Y is phenyl, Z is 3-pyrrol-1-yl-phenyl, and s is    0;-   a compound wherein Y is phenyl, Z is 4-biphenyl, s is 1, and R1 is    3-phenyl-   a compound wherein Y is phenyl, Z is    1-(5-chloropyridin-2-yl)-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-(2-methylpyridin-4-yl)-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-(4-fluorophenyl)-6-fluoro-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-(4-fluorophenyl)-4-fluoro-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-(4-cyano-3-methoxyphenyl)-indol-5-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    3-(4-trifluoromethylphenyl)-1H-indol-6-yl, and s is 0;-   a compound wherein Y is phenyl, Z is    1-phenyl-2-methyl-benzimidazol-5-yl, and s is 0;    and enantiomers, diastereomers, solvates, and pharmaceutically    acceptable salts thereof.

For use in medicine, salts of compounds of Formula (I) as herein definedrefer to non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds of Formula (I) asherein defined or of their pharmaceutically acceptable salts thereof.Suitable pharmaceutically acceptable salts of compounds of Formula (I)as herein defined include acid addition salts which can, for example, beformed by mixing a solution of the compound with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulfuricacid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoicacid, citric acid, tartaric acid, carbonic acid or phosphoric acid.Furthermore, where the compounds of Formula (I) as herein defined carryan acidic moiety, suitable pharmaceutically acceptable salts thereof mayinclude alkali metal salts, such as sodium or potassium salts; alkalineearth metal salts, such as calcium or magnesium salts; and salts formedwith suitable organic ligands, such as quaternary ammonium salts. Thus,representative pharmaceutically acceptable salts include acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate,citrate, dihydrochloride, edetate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate,malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammoniumsalt, oleate, pamoate (embonate), palmitate, pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate,subacetate, succinate, tannate, tartrate, teoclate, tosylate,triethiodide and valerate.

Representative acids and bases that may be used in the preparation ofpharmaceutically acceptable salts include acids including acetic acid,2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid,ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronicacid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuricacid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid,(±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malic acid,malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid; and bases including ammonia, L-arginine, benethamine,benzathine, calcium hydroxide, choline, deanol, diethanolamine,diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholin, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

Embodiments of the present invention include prodrugs of compounds ofFormula (I) as herein defined. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treating orpreventing embodiments of the present invention, the term“administering” encompasses the treatment or prevention of the variousdiseases, conditions, syndromes and disorders described with thecompound specifically disclosed or with a compound that may not bespecifically disclosed, but which converts to the specified compound invivo after administration to a patient. Conventional procedures for theselection and preparation of suitable prodrug derivatives are described,for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to embodiments of this invention have atleast one chiral center, they may accordingly exist as enantiomers.Where the compounds possess two or more chiral centers, they mayadditionally exist as diastereomers. It is to be understood that allsuch isomers and mixtures thereof are encompassed within the scope ofthe present invention. Furthermore, some of the crystalline forms forthe compounds may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compoundsmay form solvates with water (i.e., hydrates) or common organicsolvents, and such solvates are also intended to be encompassed withinthe scope of this invention. The skilled artisan will understand thatthe term compound as used herein, is meant to include solvated compoundsof Formula I.

Where the processes for the preparation of the compounds according tocertain embodiments of the invention give rise to mixture ofstereoisomers, these isomers may be separated by conventional techniquessuch as preparative chromatography. The compounds may be prepared inracemic form, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The compounds may, forexample, be resolved into their component enantiomers by standardtechniques, such as the formation of diastereomeric pairs by saltformation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaric acidfollowed by fractional crystallization and regeneration of the freebase. The compounds may also be resolved by formation of diastereomericesters or amides, followed by chromatographic separation and removal ofthe chiral auxiliary. Alternatively, the compounds may be resolved usinga chiral HPLC column.

One embodiment of the present invention is directed to a composition,including a pharmaceutical composition, comprising, consisting of,and/or consisting essentially of the (+)-enantiomer of a compound ofFormula (I) as herein defined wherein said composition is substantiallyfree from the (−)-isomer of said compound. In the present context,substantially free means less than about 25%, preferably less than about10%, more preferably less than about 5%, even more preferably less thanabout 2% and even more preferably less than about 1% of the (−)-isomercalculated as.

${{\% ( + )} - {enantiomer}} = {\frac{\left( {{{mass}( + )} - {enantiomer}} \right)}{\left( {{{mass}( + )} - {enantiomer}} \right) + \left( {{{mass}( - )} - {enantiomer}} \right)}100.}$

Another embodiment of the present invention is a composition, includinga pharmaceutical composition, comprising, consisting of, and consistingessentially of the (−)-enantiomer of a compound of Formula (I) as hereindefined wherein said composition is substantially free from the(+)-isomer of said compound. In the present context, substantially freefrom means less than about 25%, preferably less than about 10%, morepreferably less than about 5%, even more preferably less than about 2%and even more preferably less than about 1% of the (+)-isomer calculatedas

${{\% ( - )} - {enantiomer}} = {\frac{\left( {{{mass}( - )} - {enantiomer}} \right)}{\left( {{{mass}( + )} - {enantiomer}} \right) + \left( {{{mass}( - )} - {enantiomer}} \right)}100.}$

During any of the processes for preparation of the compounds of thevarious embodiments of the present invention, it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, Second Edition, J. F. W. McOmie, Plenum Press, 1973;T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,John Wiley & Sons, 1991; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. Theprotecting groups may be removed at a convenient subsequent stage usingmethods known from the art.

Even though the compounds of embodiments of the present invention(including their pharmaceutically acceptable salts and pharmaceuticallyacceptable solvates) can be administered alone, they will generally beadministered in admixture with a pharmaceutically acceptable carrier, apharmaceutically acceptable excipient and/or a pharmaceuticallyacceptable diluent selected with regard to the intended route ofadministration and standard pharmaceutical or veterinary practice. Thus,particular embodiments of the present invention are directed topharmaceutical and veterinary compositions comprising compounds ofFormula (I) as herein defined and at least one pharmaceuticallyacceptable carrier, pharmaceutically acceptable excipient, and/orpharmaceutically acceptable diluent

By way of example, in the pharmaceutical compositions of embodiments ofthe present invention, the compounds of Formula (I) as herein definedmay be admixed with any suitable binder(s), lubricant(s), suspendingagent(s), coating agent(s), solubilizing agent(s), and combinationsthereof.

Solid oral dosage forms, such as tablets or capsules, containing thecompounds of the present invention may be administered in at least onedosage form at a time, as appropriate. It is also possible to administerthe compounds in sustained release formulations.

Additional oral forms in which the present inventive compounds may beadministered include exilirs, solutions, syrups, and suspensions; eachoptionally containing flavoring agents and coloring agents.

Alternatively, compounds of Formula (I) as herein defined can beadministered by inhalation (intratracheal or intranasal) or in the formof a suppository or pessary, or they may be applied topically in theform of a lotion, solution, cream, ointment or dusting powder. Forexample, they can be incorporated into a cream comprising, consistingof, and/or consisting essentially of an aqueous emulsion of polyethyleneglycols or liquid paraffin. They can also be incorporated, at aconcentration of between about 1% and about 10% by weight of the cream,into an ointment comprising, consisting of, and/or consistingessentially of a white wax or white soft paraffin base together with anystabilizers and preservatives as may be required. An alternative meansof administration includes transdermal administration by using a skin ortransdermal patch.

The pharmaceutical compositions of the present invention (as well as thecompounds of the present invention alone) can also be injectedparenterally, for example intracavernosally, intravenously,intramuscularly, subcutaneously, intradermally or intrathecally. In thiscase, the compositions will also include at least one of a suitablecarrier, a suitable excipient, and a suitable diluent.

For parenteral administration, the pharmaceutical compositions of thepresent invention are best used in the form of a sterile aqueoussolution that may contain other substances, for example, enough saltsand monosaccharides to make the solution isotonic with blood.

For buccal or sublingual administration, the pharmaceutical compositionsof the present invention may be administered in the form of tablets orlozenges, which can be formulated in a conventional manner.

By way of further example, pharmaceutical compositions containing atleast one of the compounds of Formula (I) as herein defined as theactive ingredient can be prepared by mixing the compound(s) with apharmaceutically acceptable carrier, a pharmaceutically acceptablediluent, and/or a pharmaceutically acceptable excipient according toconventional pharmaceutical compounding techniques. The carrier,excipient, and diluent may take a wide variety of forms depending uponthe desired route of administration (e.g., oral, parenteral, etc.). Thusfor liquid oral preparations, such as suspensions, syrups, elixirs andsolutions, suitable carriers, excipients and diluents include water,glycols, oils, alcohols, flavoring agents, preservatives, stabilizers,coloring agents and the like; for solid oral preparations, such aspowders, capsules and tablets, suitable carriers, excipients anddiluents include starches, sugars, diluents, granulating agents,lubricants, binders, disintegrating agents and the like. Solid oralpreparations also may be optionally coated with substances, such as,sugars, or be enterically-coated so as to modulate the major site ofabsorption and disintegration. For parenteral administration, thecarrier, excipient and diluent will usually include sterile water, andother ingredients may be added to increase solubility and preservationof the composition. Injectable suspensions or solutions may also beprepared utilizing aqueous carriers along with appropriate additives,such as solubilizers and preservatives.

A therapeutically effective amount of a compound of Formula (I) asherein defined or a pharmaceutical composition thereof includes a doserange from about 0.1 mg to about 3000 mg, or any particular amount orrange therein, in particular from about 1 mg to about 1000 mg, or anyparticular amount or range therein, or, more particularly, from about 10mg to about 500 mg, or any particular amount or range therein, of activeingredient in a regimen of about 1 to about 4 times per day for anaverage (70 kg) human; although, it is apparent to one skilled in theart that the therapeutically effective amount for a compound of Formula(I) as herein defined will vary as will the diseases, syndromes,conditions, and disorders being treated.

For oral administration, a pharmaceutical composition is preferablyprovided in the form of tablets containing about 0.01, about 10, about50, about 100, about 150, about 200, about 250, and about 500 milligramsof a compound of Formula (I) as herein defined.

Advantageously, a compound of Formula (I) as herein defined may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three and four times daily.

Optimal dosages of a compound of Formula (I) as herein defined to beadministered may be readily determined and will vary with the particularcompound used, the mode of administration, the strength of thepreparation and the advancement of the disease, syndrome, condition ordisorder. In addition, factors associated with the particular subjectbeing treated, including subject gender, age, weight, diet and time ofadministration, will result in the need to adjust the dose to achieve anappropriate therapeutic level and desired therapeutic effect. The abovedosages are thus exemplary of the average case. There can be, of course,individual instances wherein higher or lower dosage ranges are merited,and such are within the scope of this invention.

Compounds of Formula (I) as herein defined may be administered in any ofthe foregoing compositions and dosage regimens or by means of thosecompositions and dosage regimens established in the art whenever use ofa compound of Formula (I) as herein defined is required for a subject inneed thereof.

As MGL Inhibitors, the compounds of Formula (I) as herein defined areuseful in methods for treating and preventing a disease, a syndrome, acondition or a disorder in a subject, including an animal, a mammal anda human in which the disease, the syndrome, the condition or thedisorder is affected by the modulation of the MGL enzyme. Such methodscomprise, consist of and/or consist essentially of administering to asubject, including an animal, a mammal, and a human in need of suchtreatment or prevention a therapeutically effective amount of acompound, salt or solvate of Formula (I) as herein defined. Inparticular, the compounds of Formula (I) as herein defined are usefulfor preventing or treating pain, or diseases, syndromes, conditions, ordisorders causing such pain, or for treating inflammation or CNSdisorders.

Examples of inflammatory pain include pain due to a disease, condition,syndrome, disorder, or a pain state, including inflammatory boweldisease, visceral pain, migraine, post operative pain, osteoarthritis,rheumatoid arthritis, back pain, lower back pain, joint pain, abdominalpain, chest pain, labor pain, musculoskeletal diseases, skin diseases,toothache, pyresis, burn, sunburn, snake bite, venomous snake bite,spider bite, insect sting, neurogenic bladder, interstitial cystitis,urinary tract infection, rhinitis, contact dermatitis/hypersensitivity,itch, eczema, pharyngitis, mucositis, enteritis, irritable bowelsyndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome,menstrual pain, endometriosis, pain, pain due to physical trauma,headache, sinus headache, tension headache, or arachnoiditis.

Examples of CNS disorders include anxieties, such as social anxiety,post-traumatic stress disorder, phobias, social phobia, special phobias,panic disorder, obsessive-compulsive disorder, acute stress, disorder,separation anxiety disorder, and generalized anxiety disorder, as wellas depression, such as major depression, bipolar disorder, seasonalaffective disorder, post natal depression, manic depression, and bipolardepression.

GENERAL SYNTHETIC METHODS

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below andillustrated in the schemes and examples that follow. Since the schemesare an illustration, the invention should not be construed as beinglimited by the chemical reactions and conditions described in theschemes. The various starting materials used in the schemes and examplesare commercially available or may be prepared by methods well within theskill of persons versed in the art. The variables are as defined herein.

Abbreviations used in the instant specification, particularly theschemes and examples, are as follows:

AcCl acetyl chloride AcOH glacial acetic acid aq. aqueous Bn or Bzlbenzyl CAN ceric ammonium nitrate conc. concentrated DBU1,8-diazabicyclo[5.4.0]undec-7-ene DCC N,N′-dicyclohexyl-carbodiimideDCE 1,2-dichloroethane DCM dichloromethane DIAD diisopropylazodicarboxylate DIPEA diisopropyl-ethyl amine DMF N,N-dimethylformamideDMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EDCN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride ESIelectrospray ionization EtOAc ethyl acetate EtOH ethanol h hour(s) HATUO-(1H-7-azabenzotriazol-1-yl)-1,1,3,3- tetramethyluroniumhexafluorophosphate HBTU O-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HEK human embryonic kidney HPLChigh performance liquid chromatography mCPBA meta-chloroperoxybenzoicacid MeCN acetonitrile MeOH methanol MeOTf methyl triflate MHz megahertzmin minute(s) MS mass spectrometry NBS N-bromosuccinimide NMR nuclearmagnetic resonance PyBrOP bromo-tris-pyrrolidinophosphoniumhexafluorophosphate RP reverse-phase R_(t) retention time TEA or Et₃Ntriethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thinlayer chromatography TMS tetramethylsilane

Scheme A illustrates a route for the synthesis compounds of Formula(I)-A, wherein R¹, s, Y, and Z are as defined herein.

A compound of formula A1, wherein PG is a conventional amino protectinggroup, such as Boc, Fmoc, Cbz, and the like, is either commerciallyavailable or may be prepared by known methods described in thescientific literature. A compound of formula A1 in the presence of anon-nucleophilic base, such as pyridine, may be treated withtrifluoroacetic anhydride to afford a compound of formula A2. Removal ofthe protecting group (PG) by conventional methods affords a compound offormula A3. A compound of formula A3 may be treated with a compound offormula A4 in the presence of a hindered amine base, such as DIPEA, toafford a compound of formula A5. Treatment of a compound of formula A5with 1-chloroethyl chloroformate followed by methanolysis affords thecorresponding amine of formula A6. Similarly, when the R¹ substituent ofa compound of formula A5 is hydroxy(C₁₋₃)alkyl, the benzhydryl group maybe removed by hydrogenation in the presence of a palladium catalyst toafford the amine of formula A6. A compound of formula A6 may be coupledwith a carboxylic acid of formula A7 wherein Q is hydroxy, in thepresence of an appropriate coupling agent such as HATU, DCC, EDC, HBTU,PyBrOP, and the like; optionally in the presence of a base such asDIPEA, to afford an amide of formula A8. Similarly, an acid chloride offormula A7 wherein Q is chloro may be used to effect the acylation of acompound of formula A6. In such case a non-nucleophilic base such aspyridine may be added to afford an amide of formula A8. Removal of thetrifluoroacetyl group of a compound of formula A8 may be accomplished bythe action of potassium carbonate or TEA in the presence of an alcoholicsolvent such as methanol to afford a compound of formula A9. A compoundof formula A9 may be acylated with a carboxylic acid or acid chloride offormula A10, wherein Q is hydroxy or chloride, respectively. Appropriatecoupling conditions when using a compound of formula A10 (wherein Q isOH) include a coupling agent, such as HATU, DCC, EDC, HBTU, PyBrOP, andthe like; and a base such as DIPEA to afford a compound of Formula(I)-A. When the acylation is effected by the addition of thecorresponding acid chloride, the addition of a non-nucleophilic basesuch as pyridine affords a compound of Formula (I)-A.

Scheme B illustrates an alternate route for the synthesis compounds ofFormula (I)-A, wherein R¹, s, Y, and Z are as defined herein.

A compound of formula A1, wherein PG is a conventional amino protectinggroup, such as Boc, Fmoc, Cbz, and the like, is either commerciallyavailable or may be prepared by known methods described in thescientific literature. A compound of formula A1 may be acylated with acompound of formula A10 using methods and reagents previously describedin Scheme A to afford a compound of formula B1. Upon conventionalremoval of the protecting group PG, a compound of formula B2 may betreated with a compound of formula A4 in the presence of a hinderedamine base such as DIPEA using the methods described in Scheme A toafford a compound of formula B3. Treatment of a compound of formula B3with 1-chloroethyl chloroformate followed by methanolysis affords thecorresponding amine of formula B4. Similarly, when the R¹ substituent ofa compound of formula B3 is hydroxy(C₁₋₃)alkyl, the benzhydryl group maybe removed by hydrogenation in the presence of a palladium catalyst toafford the amine of formula B4. An acylation reaction with a compound offormula A7 using the methods described in Scheme A affords thecorresponding compound of Formula (I)-A.

Scheme C illustrates an alternate route for the synthesis compounds ofFormula (I)-A, wherein R¹, s, Y, and Z are as defined herein.

A compound of formula B2 may be treated with a ketone of formula C1 inthe presence of decaborane or a reducing agent, such as sodiumtriacetoxyborohydride, to afford a compound of formula C2. Removal ofthe Boc-amino protecting group, using conventional reagents and methods,affords a compound of formula B4. Coupling with a compound of formula A7as described herein provides a compound of Formula (I)-A.

Scheme D illustrates a route for the synthesis compounds of Formula(I)-A, wherein R¹, s, Y, and Z are as defined herein.

A compound of formula A1, wherein PG is a conventional amino protectinggroup, such as Boc, Fmoc, Cbz, and the like, is either commerciallyavailable or may be prepared by known methods described in thescientific literature. A compound of formula A1 may be treated with acompound of formula A4 to afford a compound of formula D1. Uponconventional removal of protecting group PG, a compound of formula D2may be coupled with a compound of formula A10 (wherein Q is OH) in thepresence of a coupling agent, such as HATU, DCC, EDC, HBTU, PyBrOP, andthe like; optionally in the presence of a base such as DIPEA, to afforda compound of formula B3. When the acylation is effected by the additionof the corresponding acid chloride, the addition of a non nucleophilicbase, such as pyridine, affords a compound of formula B3. Removal of thebenzhydryl group as described herein, followed by acylation with acompound of formula A7 affords a compound of Formula (I)-A.

One skilled in the art will recognize that the synthetic sequences ofSchemes A, B, C and D may be altered so that the acylation with acompound of formula A7 precedes removal of the benzhydryl group, whichis then followed by acylation with a compound of formula A10, thusreversing the order for introduction of groups Y and Z.

Scheme E illustrates a route for the synthesis compounds of Formula(I)-E, wherein R¹, s, and Y are as defined herein, and Z is a C₆₋₁₀arylring or heteroaryl group, substituted with an optionally substitutedC₆₋₁₀aryl or heteroaryl group, as defined herein.

A compound of formula C1 may be deprotected using conventional methodsto afford the corresponding free amine of formula E1. Coupling with acarboxylic acid of formula E2, (wherein Ar_(E) is a C₆₋₁₀aryl orheteroaryl group, and said Ar_(E) is substituted with one bromo, chloro,or iodo substitutent), in the presence of a coupling agent, such asHATU, DCC, EDC, HBTU, PyBrOP, and the like; optionally in the presenceof a base such as DIPEA, affords a compound of formula E3. A ketone offormula E3 may undergo a reductive amination with a compound of formulaA1 in the presence of decaborane, sodium triacetoxyborohydride, and thelike, to afford a compound of formula E4. Upon conventional removal ofthe protecting group PG, the free amine of formula E5 may be acylatedwith a compound of formula A10 as described herein to afford a compoundof formula E6. The substituted Ar_(E) substituent of formula E6 may betreated with an appropriately substituted Ar_(E1)-boronic acid or ester(E7), or an appropriately substituted trialkyltin reagent,trialkylsilane, and the like (wherein Ar_(E1) is an optionallysubstituted C₆₋₁₀aryl or heteroaryl as defined herein), using one of avariety of coupling reactions (e.g., Suzuki, Stille, and Hiyamareactions) that are well known to those versed in the art; in thepresence of a suitable catalyst; and in the presence of a base such ascesium carbonate, sodium bicarbonate, potassium fluoride, and the like;to afford a compound of the Formula (I)-E.

Scheme F illustrates a route for the synthesis of compounds of Formula(I)-F, wherein R¹, s, and Y are as defined herein, and Z is anoptionally substituted C₆₋₁₀aryl(C₁₋₆)alkyl or C₆₋₁₀aryl(C₂₋₆)alkenylgroup, wherein L is (C₁₋₆)alkyl or (C₂₋₆)alkenyl, respectively.

A compound of formula B4 may be coupled with a commercially availablecompound of formula F2 (wherein Ar_(F) is an optionally substitutedC₆₋₁₀aryl substituent as defined herein) in the presence of a couplingagent, such as HATU, DCC, EDC, HBTU, PyBrOP, and the like; optionally inthe presence of a base, such as DIPEA; to afford a compound of Formula(I)-F.

Scheme G illustrates a route for the synthesis of compounds of Formula(I)-G and Formula (I)-G1, wherein R¹, s, and Y are as defined herein,and Z is either an optionally substituted C₆₋₁₀aryl (Ar_(G)) substitutedwith phenyl(C₂₋₆)alkynyl (Formula (I)-G) or an optionally substitutedC₆₋₁₀aryl substituted with phenyl(C₁₋₆)alkyl.

A compound of Formula G1 may be prepared according to the methodsdescribed herein, wherein Ar_(G) is C₆₋₁₀aryl and X is a substituentselected from bromo or iodo. An X-substituted Ar_(G) ring may becross-coupled with a compound of formula G2 in the presence of apalladium catalyst, copper iodide, and a base such as triethylamine toafford a compound of Formula (I)-G. The alkynyl functionality of acompound of Formula (I)-G may be reduced to the corresponding alkylgroup by transition metal catalyzed hydrogenation, using a transitionmetal such as palladium on carbon, palladium (II) hydroxide, orplatinum, under a hydrogen gas atmosphere, to afford a compound ofFormula (I)-G1.

Scheme H illustrates a route for the synthesis of compounds of Formula(I)-H, H1, H2, and H3, wherein R¹, s, and Y are as defined herein, and Zis a benzofused heterocyclyl attached via the benzo ring, wherein theheterocyclyl portion contains a nitrogen atom, and wherein the nitrogenatom is optionally substituted. For illustrative purposes only, a1,2,3,4-tetrahydroisoquinolinyl group has been selected to represent anitrogen-containing benzofused heterocyclyl of the present invention.

A compound of formula B4 may be coupled with a carboxylicacid-substituted benzofused heterocyclyl of formula H1 (wherein PG is aconventional amino protecting group) to afford a compound of formula H2.Deprotection of the amino functionality of a compound of formula H2affords the corresponding amine of Formula (I)-H, which may bederivatized using a variety of synthetic methods to form additionalcompounds of the present invention. For example, a compound of Formula(I)-H may be treated with an appropriately substituted sulfonyl chlorideof formula H3 in the presence of an organic base to afford a compound ofFormula (I)-H1 (wherein R_(H2) is phenyl or C₁₋₆alkyl. Additionally, acompound of the Formula (I)-H2 may be prepared by alkylation of theamino functionality of a compound of Formula (I)-H with an alkylatingagent of formula H4 (wherein R_(H3) is phenyl or C₁₋₆alkylcarbonyl) inthe presence of a base. LG of a compound of formula H4 is a commonleaving group, such as a bromide, iodide, tosylate, mesylate, and thelike. A compound of Formula (I)-H2 may also be prepared by a reductiveamination with a compound of formula H5 in the presence of a reducingagent, such as sodium triacetoxy borohydride. A compound of Formula(I)-H3 may be prepared via a peptide coupling reaction between acompound of Formula (I)-H and an appropriately substituted carboxylicacid of formula H6 (wherein R_(H) is an optionally substitutedcyclohexyl, C₁₋₆alkyl, or phenyl as defined herein) in the presence of asuitable coupling agent. Finally, compounds of Formula (I)-H4 of thepresent invention, wherein Ar_(H) is pyrimidine or an appropriatelysubstituted phenyl group, may be prepared by the treatment of a compoundof Formula (I)-H with a compound of formula H7 (wherein X_(H) is a groupsuch as chloro, bromo, or iodo and Ar_(H) is as defined herein) in thepresence of a transition metal catalyst, such as palladium acetate, asuitable phosphine ligand, such as BINAP, and a base, such as potassiumt-butoxide.

Scheme I illustrates a route for the synthesis of compounds of Formula(I)-I, wherein R¹, s, and Y are as defined herein and Z is a C₆₋₁₀arylsubstituted with C₆₋₁₀aryl(C₁₋₄)alkoxy as defined herein. Forillustrative purposes only, the Z—C₆₋₁₀aryl ring is depicted as a phenylgroup.

A commercially available compound of formula I1 may be converted to acompound of formula I2 by the action of a chlorinating agent such asoxalyl chloride, thionyl chloride, and the like. A compound of formulaB4 may be acylated with a compound of formula I2 to afford a compound offormula I3. Removal of the acetyl functionality of a compound of formulaI3 by hydrolysis in the presence of a nucleophilic base like lithiumhydroxide, affords the corresponding compound of formula I4. Alkylationwith a compound of formula I5 (wherein Ar₁ is an optionally substitutedC₆₋₁₀aryl group and X_(I) is I, Br, Cl, or tosylate) affords a compoundof Formula (I)-I. Similarly, Mitsunobu chemistry with a compound offormula I6 (wherein X₁ is hydroxy) may be used to prepare a compound ofFormula (I)-I.

Scheme J illustrates a route for the synthesis of compounds of Formula(I)-J, wherein R¹, s, and Y are as defined herein, and Z is a C₆₋₁₀arylsubstituted with C₆₋₁₀aryl(C₁₋₄)alkylthio as defined herein. Forillustrative purposes only, the Z C₆₋₁₀aryl ring is depicted as a phenylgroup.

A compound of formula J1 is either commercially available or may beprepared by known methods described in the scientific literature. Acompound of formula J1 may be alkylated with a compound of formula I5(wherein X_(j) is I, Br, Cl, or tosylate) to afford a compound offormula J2. Saponification of a compound of formula J2 affords acompound of formula J3 (wherein Q_(J) is hydroxy), which may be coupledwith a compound of formula B4; or the carboxylic acid may first beconverted to its corresponding acid chloride of formula J3 (whereinQ_(J) is chloro) followed by the acylation of a compound of formula B4;to afford a compound of Formula (I)-J.

Scheme K illustrates a route for the synthesis of compounds of Formula(I)-K, wherein R¹, s, and Y are as defined herein, and Z is anoptionally substituted C₆₋₁₀aryl, further substituted with phenyloxy,and wherein phenyloxy is optionally substituted with C₁₋₄alkyl,trifluoromethyl, or one to two chloro substituents as defined herein.For illustrative purposes only, the Z C₆₋₁₀aryl ring is depicted as aphenyl group.

A compound of formula K1 is either commercially available or may beprepared by known methods described in the scientific literature. Acompound of formula K1, or an optionally substituted derivative thereof,may be coupled with an aryl boronic acid of formula K2 (wherein Ar_(K)is phenyl optionally substituted with C₁₋₄alkyl, trifluoromethyl, or oneto two chloro substituents), in the presence of a copper catalyst, suchas copper iodide or copper (II) acetate, appropriate ligands, such aspyridine, 1,10-phenanthroline, ethylene diamine and the like, and anorganic base, such as triethylamine, to afford a compound of formula K3.Alternatively, compounds of formula K3 may be prepared by nucleophilicaromatic displacement of an appropriately substituted methylhalobenzoate derivative, wherein the preferred halogen substituent isfluoro, with Ar_(K)-OH, wherein Ar_(K) is as previously defined, in thepresence of a base. Saponification followed by optional treatment withan appropriate chlorinating agent affords a compound of formula K4wherein Q_(K) is hydroxy or chloro. Acylation of a compound of formulaB4 with a compound of formula K4 affords a compound of Formula (I)-K.

Scheme L illustrates a route for the synthesis of compounds of Formula(I)-L, wherein R¹, s, and Y are as defined herein, and Z is anoptionally substituted C₆₋₁₀aryl substituted with phenylthio, whereinphenylthio is optionally substituted with C₁₋₄alkyl, trifluoromethyl, orone to two chloro substituents as defined herein. For illustrativepurposes only, the Z C₆₋₁₀aryl ring is depicted as a phenyl group.

A compound of formula L1 is either commercially available or may beprepared by known methods described in the scientific literature. Anaryl bromide of formula L1, or an optionally substituted derivativethereof, may be cross coupled with a compound of formula L2 (whereinAr_(L) is phenyl optionally substituted with C₁₋₄alkyl, trifluoromethyl,or one to two chloro substituents), in the presence of a palladiumcatalyst, such as palladium tetrakis(triphenylphosphine), appropriateligands, such as triphenylphosphine, and a base, such as potassiumt-butoxide, to afford a compound of formula L3. Saponification of themethyl ester affords a compound of formula L4. A compound of formula B4may be coupled with a compound of formula L4 in the presence of anappropriate peptide coupling agent such as DCC, EDC, HBTU, PyBrOP, andthe like to afford a compound of Formula (I)-L.

Scheme M illustrates a route for the synthesis of compounds of Formula(I)-M, wherein R¹, s, and Y are as defined herein, and Z is a C₆₋₁₀arylsubstituted with phenylsulfonyl. For illustrative purposes only, the ZC₆₋₁₀aryl ring is depicted as a phenyl group.

A compound of formula M1 may be prepared according to the methodsdescribed in Scheme L. Oxidation of the thioether functionality may beaccomplished by the action of an appropriate oxidizing agent, such asmCPBA, hydrogen peroxide, and the like, to afford a compound of formulaM2. Upon saponification, and subsequent peptide coupling with a compoundof formula B4, a compound of Formula (I)-M may be prepared.

Scheme N illustrates a route for the synthesis of compounds of Formula(I)-N, wherein R¹, s, and Y are as defined herein and Z is C₆₋₁₀arylsubstituted with a 5 to 8 membered heterocyclyloxy optionallysubstituted at a nitrogen atom with phenylcarbonyl, C₁₋₄alkylcarbonyl,or C₁₋₄alkoxycarbonyl. For illustrative purposes only, the Z—C₆₋₁₀arylring is depicted as a phenyl group.

A compound of formula I4 may be coupled with a compound of formula N1(wherein R_(N) is phenyl, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylamino,C₁₋₄dialkylamino, or N-containing heterocyclyl attached via the nitrogenatom) under Mitsunobu conditions in an aprotic organic solvent, such asTHF, to afford a compound of Formula (I)-N. Mitsunobu coupling may alsobe performed between 14 and a compound of formula N2, where PG is aconventional amino protecting group, such as Boc, Fmoc, Cbz, and thelike. Subsequent removal of the protecting group (PG) by conventionalmethods affords a compound of formula N3, which may be derivatized usinga variety of synthetic methods to form additional compounds of thepresent invention. For example, a compound of formula N3 may be coupledwith a carboxylic acid (Q is hydroxy, R_(N) is phenyl or C₁₋₄alkyl),acid chloride (Q is chloride, R_(N) is phenyl or C₁₋₄alkyl),chloroformate (Q is chloride, R_(N) is C₁₋₄alkoxy), or carbamoylchloride (Q is chloride, R_(N) is C₁₋₄alkylamino, C₁₋₄dialkylamino, orN-containing heterocyclyl attached via the nitrogen atom) of formula N4as described herein to provide a compound of Formula (I)-N.Additionally, a compound of formula N3 may be reacted with a sulfamoylchloride of formula N5, where R_(N2) is C₁₋₄alkylamino,C₁₋₄dialkylamino, or N-containing heterocyclyl attached via the nitrogenatom, to afford a compound of Formula (I)-N2.

Scheme O illustrates a route for the synthesis of compounds of Formula(I)-O, wherein R¹, s, and Y are as defined herein, and Z is anoptionally substituted C₆₋₁₀aryl, further substituted with R¹, whereinR¹ is (1-R²)-pyrrolidin-3-yloxy, C₁₋₄alkyl, or C₆₋₁₀aryl(C₁₋₄)alkyl. Forillustrative purposes only, the Z—C₆₋₁₀aryl ring is depicted as a phenylgroup.

A compound of formula O1 may be coupled with a compound of formula O2(wherein X_(O) is hydroxy) under Mitsunobu conditions to afford acompound of formula O3. Alkylation may also be achieved via anucleophilic displacement reaction with a compound of formula O2(wherein X_(o) is I, Br, Cl, or tosylate) in the presence of a base toafford a compound of formula O3. Saponification of the methyl ester of acompound of formula O3 affords the corresponding carboxylic acid offormula O4. A compound of formula O4 may be coupled with a compound offormula B4 as described herein to afford a compound of Formula (I)-O.Furthermore, a compound of formula O3, where R_(O) is(1-R²)-pyrrolidin-3-yloxy and R² is a conventional amino protectinggroup, may be deprotected and additionally derivatized on thepyrrolidine nitrogen as described herein to afford, after conversion toa compound of formula O4 and subsequent coupling with a compound offormula B4, a compound of Formula (I)-O.

Scheme P illustrates a route for the synthesis of compounds of Formula(I)-P, wherein R¹, s, and Y are as defined herein, and Z is C₆₋₁₀arylsubstituted with phenyl-(Q)-C₁₋₆alkyl wherein Q is O, S, or NH; andphenyl of phenyl-(Q)-C₁₋₆alkyl is optionally independently substitutedwith one to two substitutents selected from bromo, chloro, fluoro, iodo,C₁₋₄alkyl, C₁₋₄alkoxy, and trifluoromethyl.

A compound of formula P1 (wherein X_(P) is hydroxy, chloro, or bromo) iseither commercially available or may be prepared by known methodsdescribed in the scientific literature. A compound of formula P1 mayundergo an alkylation via Mitsunobu reaction or nucleophilicdisplacement chemistry with a compound of formula P2 to afford acompound of formula P3. Saponification of the methyl ester of a compoundof formula P3 affords the corresponding carboxylic acid of formula P4. Acompound of formula P4 may be coupled with a compound of formula B4 asdescribed herein to afford a compound of Formula (I)-P.

Scheme Q illustrates the preparation of certain useful intermediates offormula A7 (Q is hydroxy) wherein Z is a heteroaryl substituted with anoptionally substituted aryl group (Ar_(Q)). For illustrative purposesonly, the heteroaryl ring is represented by an indole.

A compound of formula Q1 is either commercially available or may beprepared by known methods described in the scientific literature. Thecompound Q1 may be treated with an aryl iodide of formula Q2 in thepresence of copper iodide, trans-N,N′-dimethylcyclohexane-1,2-diamine,and potassium phosphate to afford a compound of formula Q3. Subsequentsaponification affords useful carboxylic acid intermediates of formulaQ4.

Scheme R illustrates the preparation of certain useful intermediates offormula A7 (Q is hydroxy) wherein Z is a benzimidazolyl or benzoxazolyl,and Z is substituted with an optionally substituted aryl or heteroarylgroup (Ar_(R)) or with Ar_(R)(C₁₋₄)alkyl.

A compound of formula R1 is either commercially available or may beprepared by known methods described in the scientific literature. Thecompound R1 may be treated with an aryl or heteroaryl substitutedcarboxylic acid of formula R2 in the presence of a coupling agent suchas DCC, and a hindered base such as DMAP, in an aprotic organic solventto afford a compound of formula R3. Acid catalyzed ring closure of acompound of formula R3 affords the substituted benzimidazole orbenzoxazole of formula R4 or R6, respectively. Subsequent saponificationaffords useful carboxylic acid intermediates of formula R5 or R7.

Scheme S illustrates the preparation of certain useful intermediates offormula A7 (Q is hydroxy) wherein Z is an optionally substitutedbenzothienyl group, and R_(S) represents appropriate substituents asdefined in Formula (I).

A compound of formula S1 is either commercially available or may beprepared by known methods described in the scientific literature. Thecompound of formula S1 may be treated with thionyl chloride in anaprotic organic solvent, followed by treatment with methanol to afford acompound of formula S2. Subsequent saponification affords usefulcarboxylic acid intermediates of formula S3. One skilled in the art willrecognize that asymmetrically substituted compounds of formula S1 couldlead to mixtures of positional isomers upon cyclization with thionylchloride. The isomers may then be separated and isolated usingconventional chromatography known to those skilled in the art.

Scheme T illustrates the preparation of certain useful intermediates offormula A7 (Q is hydroxy) wherein Z is a C₆₋₁₀aryl (Ar_(T)) substitutedby an optionally substituted C₆₋₁₀arylmethyl group.

A compound of formula T1 is either commercially available or may beprepared by known methods described in the scientific literature. Thecompound of formula T1 may be treated with an appropriately substitutedorganometallic reagent, such as an Ar_(T1)-methylzinc chloride offormula T2, in the presence of a palladium catalyst to afford a compoundof formula T3. Subsequent saponification affords useful carboxylic acidintermediates of formula T4.

Scheme U illustrates the preparation of certain useful intermediates offormula A7 (Q is hydroxy) wherein Z is a benzothienyl group substitutedwith a fluoro substituent and an optionally substituted C₆₋₁₀aryl orheteroaryl group (Ar_(E1)).

A compound of formula U1 is either commercially available or may beprepared by known methods described in the scientific literature. Thecompound of formula U1 may be cross-coupled with a boronic acid or ester(E7) in the presence of a palladium catalyst; and in the presence of asuitable base such as potassium carbonate to afford a compound offormula U2. Saponification affords the corresponding carboxylic acid U3,which may be treated with N-fluorobenzenesulfonimide in the presence ofan organometallic base such as n-butyllithium, to afford the fluorinatedcompound of formula U4.

Scheme V illustrates the preparation of certain useful intermediates offormulae V6, V8, and V10 (Q is hydroxy) wherein Z is a benzimidazolylgroup substituted with an Ar_(y) group (wherein Ar_(V) is an optionallysubstituted aryl or heteroaryl substituent as defined in Formula (I))and optionally substituted in the 2-position with methyl or oxo.

A compound of formula V1 is either commercially available or may beprepared by known methods described in the scientific literature. Thecompound of formula V1 may be treated with a compound of formula V2 toafford a compound of formula V3. The amino group may be reduced by theaction of tin chloride in an alcoholic solvent, or by palladiumcatalyzed hydrogenation to afford the diamine of formula V4. Treatmentwith trimethyl orthoformate affords a benzimidazole of formula V5, whichmay be saponified to afford a compound of formula V6.

A compound of formula V4 may be treated with trimethyl orthoacetatefollowed by saponification to afford the corresponding 2-methylsubstituted benzimidazole, V8. Similarly, a compound of formula V4 maybe treated with 1,1′-carbonyldiimidazole in DMF, followed bysaponification to afford the corresponding 2-oxo substitutedbenzimidazole, V10.

Example 1

A. 4-(2,2,2-Trifluoro-acetyl)-piperazine-1-carboxylic acid tert-butylester, 1c

To a solution of piperazine-1-carboxylic acid tert-butyl ester (1a, 10g,53.69 mmol) and pyridine (8.7 mL, 107.57 mmol) in CH₂Cl₂ (100 mL) wasadded dropwise compound 1b (10.5 mL, 75.54 mmol) at 0° C. The mixturewas stirred at 0° C. for 2 h. 2N HCl (60 mL) was added to the mixture.The organic layer was dried over MgSO₄, filtered, and then concentrated.The crude compound 1c was used in the next reaction without furtherpurification. MS m/z (MH⁺-Boc) 183.1, (MH⁺-C₄H₉) 227.1; ¹H NMR (300 MHz,CDCl₃): δ 3.45-3.7 (m, 8H), 1.5 (s, 9H).

B. 2,2,2-Trifluoro-1-piperazin-1-yl-ethanone, 1d. To a solution ofcompound 1c

(15.15 g, 53.69 mmol) in CH₂Cl₂ (60 mL) was added trifluoroacetic acid(18 mL) at room temperature. The mixture was stirred at room temperaturefor 18 h. The solvent was removed by evaporation. Ether (100 mL) wasadded to the residue. The white solid was collected by filtration,washed with ether, and dried under vacuum. The crude compound 1d wasused in the next reaction without further purification. MS m/z (M+H⁺)183.1.

C.1-[4-(1-Benzhydryl-azetidin-3-yl)-piperazin-1-yl]-2,2,2-trifluoro-ethanone,1f

To a solution of compound 1d (6 g, 32.94 mmol) and compound 1e (12.5 g,39.38 mmol) in CH₃CN (60 mL) was added DIPEA (12 mL, 68.89 mmol) at roomtemperature. The mixture was refluxed for 2 h. The solvent was removedby evaporation and the residue was partitioned between CH₂Cl₂ and aqNaHCO₃. The organic layer was washed with aq NaHCO₃ (2×) and thenextracted with 1N HCl (2×). The aqueous layer was cooled and then the pHadjusted with 1N NaOH until basic (pH=10). The mixture was extractedwith CH₂Cl₂ (2×). The organic layer was dried over MgSO₄ andconcentrated. Compound 1f was purified by reverse phase chromatography.MS m/z (M+H⁺) 404.2.

D. 1-(4-Azetidin-3-yl-piperazin-1-yl)-2,2,2-trifluoro-ethanone, 1g

To a solution of compound 1f (2.11 g, 5.23 mmol) in CH₂Cl₂ (60 mL) wasadded 1-chloroethyl chloroformate (2.0 mL, 18.35 mmol) at 0° C. underN₂. The mixture was stirred at 0° C. for 90 min and then MeOH (4 mL) wasadded. The mixture was refluxed for 1 h. Upon cooling, Et₂O (50 mL) wasadded to the mixture. The resulting solid was collected by filtrationand dried. The crude compound 1g was used in the next reaction withoutfurther purification. MS m/z (M+H⁺) 238.1.

E.1-{4-[1-(4-Cyclohexyl-benzoyl)-azetidin-3-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone,1i

To a solution of compound 1g (2.5 g, 10.54 mmol) and HATU (4 g, 10.52mmol) in DMF (25 mL) was added DIPEA (5 mL, 28.70 mmol). The mixture wasstirred at room temperature for 30 min, and then compound 1h (2 g, 9.79mmol) was added to the mixture. The reaction was stirred at roomtemperature for 18 h. Water (40 mL) was added to the reaction. Themixture was extracted with EtOAc (2×20 mL). The organic layer was driedover MgSO₄, filtered, and concentrated. The crude compound 1i waspurified by reverse phase chromatography. MS m/z (M+H⁺) 424.2.

F. (4-Cyclohexyl-phenyl)-(3-piperazin-1-yl-azetidin-1-yl)-methanone, 1j

To a solution of compound 1i (0.95 g, 2.24 mmol) in CH₃OH (16 mL) andH₂O (4 mL) was added K₂CO₃ (0.8 g, 5.79 mmol). The mixture was stirredat room temperature for 1 h. After filtration, the solvent was removedby evaporation. The crude compound 1j was used in the next reactionwithout further purification. MS m/z (M+H⁺) 328.2.

G.1-{1[(4-Cyclohexylphenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)-piperazine,Cpd 1

To a solution of compound 1j (0.08 g, 0.24 mmol) and HATU (0.093 g, 0.24mmol) in DMF (3 mL) was added DIPEA (0.1 mL). The mixture was stirred atroom temperature for 30 min, and then compound 1k (0.03 g, 0.25 mmol)was added to the mixture. The reaction mixture was stirred at roomtemperature for 18 h. Water (6 mL) was added to the mixture. The mixturewas extracted with EtOAc (2×6 mL). The organic layer was dried overMgSO₄, filtered, and concentrated. The crude compound 1 was purified byreverse phase chromatography. ¹H NMR (300 MHz, CD₃OD): δ 7.58 (d, 2H),7.44-7.53 (m, 5H), 7.34 (d, 2H), 4.6 (m, 1H), 4.42 (m, 2H), 4.27 (m,1H), 3.85 (m, 5H), 3.05 (m, 4H), 2.57 (m, 1H), 1.85 (m, 5H), 1.45 (m,5H). MS m/z (M±H⁺) 432.3.

Following the procedure described above for Example 1 and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Characterization Data 21-{1-[(4-Cyclohexylphenyl)carbonyl]azetidin-3-yl}-4-(furan-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.71 (d, 1H), 7.59(d, 2H), 7.34 (d, 2H), 7.13 (d, 1H), 6.62 (dd, 1H), 4.62 (m, 1H), 4.52(m, 1H), 4.42 (m, 1H), 4.31 (m, 1H), 4.05 (m, 4H), 3.98(m, 1H), 3.18 (m,4H), 2.58 (m, 1H), 1.84 (m, 5H), 1.24-1.52 (m, 5H) MS m/z (M + H⁺) 422.23 1-{1-[(4-Cyclohexylphenyl)carbonyl]azetidin-3-yl}-4-[(1-methyl-1H-imidazol-2-yl)carbonyl]piperazine MS m/z (M + H⁺) 436.2 41-{1-[(4-Cyclohexylphenyl)carbonyl]azetidin-3-yl}-4-(pyridin-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 433.2 51-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine¹H NMR (300 MHz, CD₃OD): δ 7.65 (m, 4H), 7.56 (d, 2H), 7.25-7.46 (m,8H), 4.58 (m, 1H), 4.49 (m, 1H), 4.35 (m, 1H), 4.26 (m, 1H), 3.92 (m,1H), 3.78 (m, 4H), 3.09 (m, 4H) MS m/z (M + H⁺) 426.1 61-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(furan-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.66 (m, 4H), 7.62 (d,1H), 7.56 (d, 2H), 7.38 (t, 2H), 7.30 (m, 1H), 7.03 (d, 1H), 6.51 (dd,1H), 4.56 (m, 1H), 4.44 (m, 1H), 4.33 (m, 1H), 4.22 (m, 1H), 3.95 (m,4H), 3.81 (m, 1H), 3.01 (m, 4H) MS m/z (M + H⁺) 416.2 71-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 8.97 (s, 1H), 8.14 (s,1H), 7.66 (m, 4H), 7.56 (d, 2H), 7.37 (t, 2H), 7.30 (m, 1H), 4.60 (m,1H), 4.49 (m, 1H), 4.37 (m, 1H), 4.27 (m, 1H), 4.08 (m, 4H), 3.95 (m,1H), 3.14 (m, 4H) MS m/z (M + H⁺) 433.2 81-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-5-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.08 (s, 1H), 8.11 (s,1H), 7.66 (m, 4H), 7.56 (d, 2H), 7.38 (t, 2H), 7.30 (m, 1H), 4.54 (m,1H), 4.39 (m, 1H), 4.31 (m, 1H), 4.17 (m, 1H), 3.84 (m, 4H), 3.73 (m,1H), 2.92 (m, 4H) MS m/z (M + H⁺) 433.2 91-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.88 (d, 1H), 7.78 (d,1H), 7.66 (m, 4H), 7.57 (d, 2H), 7.38 (t, 2H), 7.30 (m, 1H), 4.62 (m,3H), 4.48 (m, 1H), 4.37 (m, 1H), 4.26 (m, 1H), 3.91 (m, 3H), 3.13 (m,4H) MS m/z (M + H⁺) 433.2 101-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(2-methyl-1,3-thiazol-4-yl)carbonyl]piperazine MS m/z (M + H⁺) 447.1 111-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperazine MS m/z (M + H⁺) 429.3 121-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5-bromofuran-2-yl)carbonyl]piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.76 (m, 4H), 7.66(d, 2H), 7.47 (t, 2H), 7.39 (m, 1H), 7.11 (d, 1H), 6.64 (d, 1H), 4.66(m, 1H), 4.57 (m, 1H), 4.44 (m, 1H), 4.34 (m, 1H), 3.91-4.10 (m, 5H),3.17 (m, 4H) MS m/z (M + H⁺) 494.1/496.0 131-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(thiophen-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.75 (m, 4H), 7.61-7.72(m, 3H), 7.34-7.52 (m, 4H), 7.14 (t, 1H), 4.65 (m, 1H), 4.52 (m, 1H),4.42 (m, 1H), 4.29 (m, 1H), 3.96 (m, 4H), 3.90 (m, 1H), 3.07 (m, 4H) MSm/z (M + H⁺) 432.1 (calculated for C₂₅H₂₅N₃O₂S, 431.56) 141-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5-methylthiophen-2-yl)carbonyl]piperazine MS m/z (M + H⁺) 446.1 151-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5-bromothiophen-2-yl)carbonyl]piperazine MS m/z (M + H⁺) 510.1/512.1 161-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5-chlorothiophen-2-yl)carbonyl]piperazine MS m/z (M + H⁺) 466.1/467.1 171-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(3-bromothiophen-2-yl)carbonyl]piperazine MS m/z (M + H⁺) 510.0/512.1 181-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(4-bromothiophen-2-yl)carbonyl]piperazine MS m/z (M + H⁺) 510.0/512.1 191-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(thieno[3,2-b]thiophen-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 488.1 201-(1-Benzothiophen-2-ylcarbonyl)-4-[1-(biphenyl-4-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 482.1 211-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(3-methoxythiophen-2-yl)carbonyl]piperazine MS m/z (M + H⁺) 462.1 221-{1-[(4-Bromo-2-methylphenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 442.22/444.19 231-{1-[(4-Bromo-3-methoxyphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 465.0/467.1 241-{1-[(4-Bromo-3-methoxyphenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 458.1/460.0 251-{1-[(4-Bromo-2-chlorophenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 469.04/471.04 261-{1-[(4-Bromo-2-chlorophenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 462.11/464.11 5811-(Phenylcarbonyl)-4-[1-({4-[5-(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 500 13822-Phenyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 474 10711-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({4-[5-(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)azetidin-3- yl]piperazineMS m/z (M + H⁺) 507 1361 1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[5-(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)azetidin-3- yl]piperazineMS m/z (M + H⁺) 507

Example 1a

H. Methyl 1-(4-fluorophenyl)-indole-5-carboxylate, 1m

A mixture of methyl indole-5-carboxylate 1j (0.5 g, 2.85 mmol),1-bromo-4-fluoro-benzene 1k (2 mL, 18.21 mmol), CuI (0.544 g, 2.85mmol), and K₂CO₃ (0.591 g, 4.28 mmol) was heated under microwave at 220°C. for 2.5 hours. The reaction mixture was diluted with CH₂Cl₂ andfiltered. The solution was concentrated and the residue was purified byflash column chromatography (silica gel, 15% EtOAc/heptane) to give 1m(0.58 g).

I. 1-(4-fluorophenyl)-indole-5-carboxylic acid, 1n

A mixture of methyl 1-(4-fluorophenyl)-indole-5-carboxylate 1m (0.58 g,2.15 mmol) and LiOH H₂O (0.36 g, 8.6 mmol) in THF (15 mL) and H₂O (10mL) was stiffed at room temperature for 5 days. Aqueous 10% HCl solutionwas added to the reaction mixture to adjust pH=3˜4. The resultingmixture was extracted with EtOAc (2×). The organic solution was washedwith aq. NaCl, dried over Na₂SO₄ and concentrated to give 1n (0.5 g).

J.1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole,Cpd 487

The title compound, Cpd 487, was prepared according to Example 1 usingintermediate 1n from Example 1a and intermediate 1g in Example 1 asstarting materials. ¹H NMR (400 MHz, CD₃OD): δ 8.00 (d, J=1.2 Hz, 1H),7.88 (d, J=3 Hz, 1H), 7.55 (m, 2H), 7.46 (m, 3H), 7.34 (d, J=3 Hz, 1H),7.27-7.21 (m, 2H), 6.74 (d, J=3 Hz, 1H), 4.52 (bs, 1H), 4.43-4.20 (m,4H), 4.14 (m, 1H), 3.95-3.80 (m, 2H), 3.25 (m, 1H), 2.60-2.40 (m, 4H).MS m/z (M+H⁺) 490.

Following the procedure described above for Example 1a, steps H and I,and substituting the appropriate reagents, starting materials, andpurification methods known to those skilled in the art, the followingintermediate compounds were prepared:

Following the procedure described above for Example 1a, step J, andsubstituting the appropriate reagents, starting materials, andpurification methods known to those skilled in the art, the followingcompounds of the invention were prepared:

Cpd Cpd Name and Data 5671-(4-Fluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole ¹H NMR (400 MHz, CD₃OD): d 7.99 (s,1H), 7.55-7.21 (m, 12H), 6.73 (s, 1H), 4.37 (bs, 1H), 4.25 (m, 2H), 4.10(bs, 1H), 3.90 (bs, 1H), 3.75 (bs, 1H), 3.48 (bs, 2H), 3.24 (m, 1H),2.50-2.20 (m, 4H). MS m/z (M + H⁺) 483 5871-Phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indazole MS m/z (M + H⁺) 466 5791-(2,4-Difluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 501 13565-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[3-(trifluoromethyl)phenyl]-1H-indole. MS m/z (M + H⁺)540 1408 5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[3-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺)540 1357 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole ¹H NMR (400 MHz,CD₃OD): d 8.00 (s, 1H), 7.88 (d, J = 3 Hz, 1H), 7.81 (d, J = 8.6 Hz,2H), 7.64 (d, J = 8.6 Hz, 2H), 7.59 (s, 2H), 7.54 (d, J = 3 Hz, 1H),7.41 (d, J = 3.5 Hz, 1H), 6.79 (d, J = 3.5 Hz, 1H), 4.53 (bs, 1H), 4.43(m, 2H), 4.28 (m, 2H), 4.14 (bs, 1H), 3.86 (m, 2H), 3.26 (m, 1H), 2.50(m, 4H). MS m/z (M + H⁺) 540 13581-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 490 1359 5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺)540 1163 1-Phenyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indazole MS m/z (M + H⁺) 473 13601-Phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indazole ¹H NMR (400 MHz, CD₃OD): d 8.27(s, 1H), 8.11 (s, 1H), 7.88 (d, J = 3 Hz, 1H), 7.77 (m, 2H), 7.72 (d, J= 8 Hz, 2H), 7.56 (m, 3H), 7.41 (t, J = 8 Hz, 1H), 4.53 (bs, 1H),4.44-4.28 (m, 4H), 4.15 (m, 1H), 3.86 (m, 2H), 3.28 (m, 1H), 2.50 (m,4H). MS m/z 490 (M + H⁺) MS m/z (M + H⁺) 473 13641-(2,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 508 1139 1-(2,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole ¹H NMR(CDCl₃, 400 MHz): d = 8.79 (d, J = 2.0 Hz, 1 H), 7.93-8.09 (m, 2 H),7.39-7.64 (m, 2 H), 7.18-7.34 (m, 2 H), 6.98-7.16 (m, 2 H), 6.76 (d, J =3.1 Hz, 1 H), 4.20-4.51 (m, 3 H), 4.13 (d, J = 3.9 Hz, 1 H), 3.92 (br.s., 3 H), 3.67-3.84 (m, 1 H), 3.18-3.32 (m, 1 H), 2.49 (br. s., 4 H). MSm/z (M + H⁺) 508 1061 1-(2,4-Difluorophenyl)-5-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 490

Following the procedure described above for Example 1a, steps H and I,and substituting the appropriate reagents, starting materials, andpurification methods known to those skilled in the art, the followingintermediate compounds were prepared:

Following the procedure described above for Example 1a, step J, with theexception of using dioxane as a solvent in step A, and substituting theappropriate reagents, starting materials, and purification methods knownto those skilled in the art, the following compounds of the presentinvention were prepared:

Cpd Cpd Name and Data 5955-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-pyrimidin-2-yl-1H-indole MS m/z (M + H⁺) 467 5981-(5-Fluoropyrimidin-2-yl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z(M + H⁺) 485 1174 1-Pyrimidin-2-yl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole ¹H NMR(CDCl₃, 400 MHz): d = 8.83 (d, J = 8.6 Hz, 1 H), 8.73 (d, J = 4.7 Hz, 2H), 8.33 (d, J = 3.9 Hz, 1 H), 7.80-8.02 (m, 2 H), 7.64 (dd, J = 8.8,1.8 Hz, 1 H), 7.54 (d, J = 3.1 Hz, 1 H), 7.10 (t, J = 4.9 Hz, 1 H), 6.75(d, J = 3.5 Hz, 1 H), 4.03-4.72 (m, 6 H), 3.86 (m, 2 H), 3.08-3.37 (m, 1H), 2.31- 2.68 (m, 3 H). MS m/z (M + H⁺) 474 12011-Pyrimidin-2-yl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 474 1248 1-(5-Fluoropyrimidin-2-yl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 492 1147 1-(5-Fluoropyrimidin-2-yl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 492

Example 1b

K. Methyl 1-(3,4-difluorophenyl)-indole-5-carboxylate, 1p

A mixture of methyl indole-5-carboxylate 1j (2 g, 11.4 mmol),1-iodo-3,4-difluoro-benzene 1o (1.5 mL, 12.5 mmol), CuI (0.22 g, 1.14mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.54 mL, 3.43 mmol),and K₃PO₄ (6.06 g, 28.5 mmol) in toluene (12 mL) was heated at 110° C.for 7 hours. The reaction mixture was diluted with CH₂Cl₂ and filtered.The solution was concentrated and the residue was purified by flashcolumn chromatography (silica gel, 20% EtOAc/heptane) to give 1p (3.0g).

L. 1-(3,4-Difluorophenyl)-indole-5-carboxylic acid, 1q

A mixture of methyl 1-(3,4-difluorophenyl)-indole-5-carboxylate 1p (3.0g, 10.4 mmol) and LiOH (1.0 g, 41.8 mmol) in THF (120 mL) and H₂O (60mL) was stirred at room temperature for 5 days. Aqueous 10% HCl solutionwas added to the reaction mixture to adjust pH=3˜4. The resultingmixture was extracted with EtOAc (2×). The organic solution was washedwith aq. NaCl, dried over Na₂SO₄ and concentrated to give 1q (2.85 g).

M.1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole,Cpd 1362

The title compound, Cpd 1362, was prepared according to Example 1 usingintermediate 1q from Example 1b and intermediate 1g in Example 1 asstarting materials. ¹H NMR (CDCl₃,400 MHz): d=7.99 (d, J=1.6 Hz, 1H),7.88 (d, J=3.1 Hz, 1H), 7.44-7.64 (m, 3H), 7.18-7.44 (m, 4H), 6.75 (d,1H), 4.47-4.63 (m, 1H), 4.19-4.47 (m, 4H), 4.07-4.19 (m, 1H), 3.89 (br.s., 2H), 3.18-3.33 (m, 1H), 2.50 (t, J=5.1 Hz, 4H). MS m/z (M+H⁺) 508.

Following the procedure described above for Example 1b, steps K and L,and substituting the appropriate reagents, starting materials, andpurification methods known to those skilled in the art, the followingintermediate compounds were prepared:

Following the procedure described above for Example 1b, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 13631-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR(CDCl₃, 400 MHz): d = 8.79 (d, J = 2.0 Hz, 1 H), 8.00 (dd, J = 11.5, 1.8Hz, 2 H), 7.44-7.65 (m, 2 H), 7.18- 7.42 (m, 4 H), 6.75 (d, J = 3.5 Hz,1 H), 4.20-4.46 (m, 3 H), 4.13 (br. s., 1 H), 3.93 (br. s., 3 H),3.67-3.85 (m, 1 H), 3.17-3.36 (m, 1 H), 2.49 (br. s., 4 H) MS m/z 508(M + H⁺) 1366 1-(3,4-Difluorophenyl)-5-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR(CDCl₃, 400 MHz): d = 9.42-9.61 (m, 1 H), 7.99 (s, 1 H), 7.54-7.64 (m, 1H), 7.45-7.54 (m, 1 H), 7.15-7.43 (m, 4 H), 6.93 (s, 1 H), 6.75 (d, J =3.1 Hz, 1 H), 6.52 (br. s., 1 H), 6.18-6.31 (m, 1H), 4.19-4.42 (m, 3 H),4.08-4.19 (m, 1 H), 3.90 (br. s., 4 H), 3.24 (s, 1 H), 2.34-2.56 (m, 4H) MS m/z 490 (M + H⁺) 6035-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-pyridin-4-yl-1H-indole MS m/z (M + H⁺) 466.1 6301-(2-Methylpyridin-4-yl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)- 1H-indole MS m/z(M + H⁺) 480.1 1192 1-Pyridin-3-yl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 473.2 12471-Pyridin-3-yl-5-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 456.3 11271-Pyridin-4-yl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 473.0 1072 1-(6-Methoxypyridin-3-yl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 503.2 1176 1-(6-Methoxypyridin-3-yl)-5-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 485.4 1105 1-(6-Methylpyridin-3-yl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 487.3 1181 1-(6-Methylpyridin-3-yl)-5-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 469.3 1062 5-({3-[4-(1H-Pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-1H- indole MS m/z(M + H⁺) 523.2 13125-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-1H- indole MS m/z(M + H⁺) 541.3 1107 1-(2-Methoxypyridin-4-yl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 503.0 1263 1-Pyrimidin-5-yl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 474.1 1410 1-(2-Methylpyridin-4-yl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 487.0 586 5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-indole MS m/z (M +H⁺) 534.1 596 1-(5-Fluoropyridin-2-yl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)- 1H-indole MS m/z(M + H⁺) 484.0 1135 1-Pyridin-2-yl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 473.2 11891-Pyridin-2-yl-5-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 455.2 10731-(5-Methylpyridin-2-yl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 509.0 1126 1-(6-Methylpyridin-2-yl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 487.3 1128 1-(4-Methylpyridin-2-yl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 487.2 1216 1-(2-Methylpyrimidin-4-yl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 488.0 13145-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H- indole MS m/z(M + H⁺) 541.0 1121 1-(5-Fluoropyridin-2-yl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 491.0 1197 1-(4-Methylpyridin-2-yl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 487.1 13375-({4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole ¹H NMR (400 MHz,CDCl₃): δ 9.06 (s, 1H); 8.4 (s, 1H); 7.9-7.68 (m, 8H); 7.4 (ar, 1H);4.97 (m, 2H); 4.45 (m, 2H); 4.16 (bs, 1H); MS m/z (M + H⁺) 508.0 13385-({4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole ¹H NMR (400 MHz,CDCl₃): δ 7.91 (m, 1H); 7.81 (m, 4H); 7.70 (m, 2H); 7.60 (m, 2H); 7.30(m, 1H); 6.75 (m, 1H); 5.01-4.84 (m, 2H); 4.37 (m, 2H); 4.09 (bm, 1H) MSm/z (M + H⁺) 540.2 13395-({3-[4-(1H-Pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺)522.2 1097 5-({3-[4-(Isothiazol-5-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole ¹H NMR (400 MHz,CDCl₃): δ 8.44 (s, 1H); 7.94 (s, 1H); 7.80 (m, 2H); 7.69 (m, 2H); 7.59(m, 2H); 7.49 (m, 2H); 6.77 (m, 1H); 4.65-4.15 (bm, 3H); 3.81 (bm, 4H);3.0 (bm, 4H) MS m/z (M + H⁺) 540.2 12301-(4-Fluorophenyl)-3-methyl-5-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 504.1 1089 1-(4-Fluorophenyl)-3-methyl-5-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H- indole ¹H NMR (400MHz, CDCl₃): δ 7.92 (d, 1H); 7.78 (d, 1H); 7.69 (m, 1H); 7.42 (m, 3H);7.21 (m, 6H); 4.94 (m, 1H); 4.40 (dd, 1H); 4.25 (dd, 1H); 4.0 (bm, 1H);3.85 (bm, 3H); 3.15 (bm, 3H); 2.3 (s, 3H) MS m/z (M + H⁺) 504.1 11205-({4-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺)522.1 1134 1-(3,4-Difluorophenyl)-3-methyl-5-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H- indole ¹H NMR (400MHz, CDCl₃): δ 8.0 (s, 1H); 7.86 (s, 1H); 7.80 (s, 1H); 7.62-7.42 (m,3H); 7.36 (m, 3H); 5.05 (m, 1H); 4.5 (m, 1H); 4.35 (m, 1H); 4.08 (bm,1H); 3.94 (bm, 4H); 3.24 (m, 3H) MS m/z (M + H⁺) 522.2 12191-(3,4-Difluorophenyl)-3-methyl-5-({4-[1-(1H-pyrrol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 465.1

Example 1c

N.1-(5-Methylpyridin-2-yl)-5-({3-[4-(trifluoroacetyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole;Cpd 1184

The title compound, Cpd 1184, was prepared according to Example 1 usingintermediate 1r from Example 1b and intermediate 1g in Example 1 asstarting materials. MS m/z (M+H⁺) 472.1

Following the procedure described above for Example 1c, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Salt Cpd Cpd Name and Data Form 1409 1-(5-Chloropyridin-2-yl)-5-({3-[4-N-TFA (trifluoroacetyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1H-indoleMS m/z (M + H⁺) 492.1 1199 1-(4-Methylpyridin-2-yl)-5-({3-[4- N-TFA(trifluoroacetyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1H-indole MSm/z (M + H⁺) 472.1 656 1-(1-{[3-Chloro-6-(trifluoromethyl)-1- N-TFAbenzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(trifluoroacetyl)piperazine MS m/z (M + H⁺) 500.1 10791-(4-Fluorophenyl)-5-({3-[4- N-TFA(trifluoroacetyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1H-indole MSm/z (M + H⁺) 475.2

Example 1d

O. Methyl 2-phenyl-benzooxazole-6-carboxylate, 1u

A mixture of methyl 4-amino-3-hydroxy-benzoate is (0.3 g, 1.8 mmol) andbenzoyl chloride 1t (0.23 mL, 2.0 mmol) in dioxane (2.5 mL) was heatedat 210° C. under microwave for 15 min. The reaction mixture was dilutedwith CH₂Cl₂ and washed with aq. NaHCO₃. The organic solution was driedover Na₂SO₄, concentrated and purified by flash column chromatography(silica gel, 20% EtOAc/heptane) to give 1u (0.39 g).

P. 2-Phenyl-benzooxazole-6-carboxylic acid, 1v

A mixture of methyl 2-phenyl-benzooxazole-6-carboxylate 1u (0.37 g, 1.46mmol) and LiOH (0.10 g, 4.2 mmol) in THF (4 mL), MeOH (4 mL), and H₂O (4mL) was stiffed at room temperature for 6 h. Aqueous 1N HCl solution wasadded to the mixture to adjust pH to 3-4. The resulting mixture wasextracted with EtOAc (2×). The organic solution was washed with aq.NaCl, dried over Na₂SO₄ and concentrated to give 1t (0.34 g).

Following the procedure described above for Example 1d and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Following the procedure described above for Example 1, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 11412-Phenyl-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 474 11516-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-[3-(trifluoromethyl)phenyl]-1,3- benzoxazole MS m/z(M + H⁺) 542 11586-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-[3-(trifluoromethyl)phenyl]-1,3- benzoxazole MS m/z(M + H⁺) 542

Example 1e

Q. Ethyl 2-phenyl-benzothiazole-6-carboxylate, 1y

A mixture of ethyl 2-bromo-benzothiazole-6-carboxylate 1w (300 mg, 1.05mmol), phenylboronic acid 1x (192 mg, 1.57 mmol), K₂CO₃ (188 mg, 1.36mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (43 mg, 0.05 mmol) in dioxane (2 mL) andH₂O (0.4 ml) was heated at 120° C. for 25 min under microwave. Thereaction mixture was diluted with CH₂Cl₂, washed with H₂O, dried overNa₂SO₄, and concentrated. Purification by flash column chromatography(silica gel, 15% EtOAc/heptane) gave 1y (220 mg).

R. 2-Phenyl-benzothiazole-6-carboxylic acid, 1z

Ethyl 2-phenyl-benzothiazole-6-carboxylate 1y (220 mg, 0.78 mmol) wasstiffed with LiOH (74 mg, 3.1 mmol) in THF (4 mL) and H2O (4 mL) for 16h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3˜4.The resulting mixture was extracted with EtOAc (2×). The organicsolution was washed with aq. NaCl, dried over Na₂SO₄ and concentrated togive 1z (200 mg).

Following the procedure described above for Example 1e and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following intermediate compoundwas prepared:

Following the procedure described above for Example 1, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 5922-Phenyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole MS m/z (M + H⁺) 483 11252-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole ¹H NMR (400 MHz, CD₃OD): d8.25 (s, 1H), 8.12-8.06 (m, 3H), 7.88 (d, J = 3 Hz, 1H), 7.74 (d, J = 8Hz, 1H), 7.53 (m, 4H), 4.53 (bs, 1H), 4.4-4.26 (m, 4H), 4.15 (m, 1H),3.86 (m, 2H), 3.27 (m, 1H), 2.50 (m, 4H) MS m/z (M + H⁺) 490 11872-Phenyl-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole MS m/z 490 (M + H⁺)

Example 1f

Q. Methyl 1-(5-chloropyridin-2-yl)-1H-indole-5-carboxylate, 1bb

A mixture of 1j (1.14 mmol, 200 mg), 1aa (1.14 mmol, 150 mg), K₂CO₃(2.28 mmol, 315 mg) and NMP (1.5 mL) was heated at 200° C. in amicrowave reactor for 2 h. The mixture was poured into water (50 mL) andextracted with EtOAc. The organic layer was washed with brine, driedover Na₂SO₄ and concentrated under vacuo. Purification was carried byflash column chromatography (silica gel, 15% EtOAc/heptane) to give 290mg of 1bb (290 mg).

R. (5-Chloropyridin-2-yl)-1H-indole-5-carboxylic acid, 1cc

A mixture of 1bb (0.942 mmol, 270 mg), LiOH (3.77 mmol, 90 mg), THF (3mL), MeOH (3 mL), and H₂O (3 mL) was stirred at room temperature forovernight. The reaction mixture was acidified with 1N aqueous HCl topH=5. The solid precipitate was filtered, washed with EtOAc, and driedunder vacuo to give 202 mg of 1cc.

Following the procedure described above for Example 1, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 13131-(5-Chloropyridin-2-yl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR(CDCl₃) d: 8.52 (d, J = 2.2 Hz, 1H), 8.21 (d, J = 8.6 Hz, 1H), 7.96 (s,1H), 7.88 (d, J = 3.2 Hz, 1H), 7.81 (dd, J = 8.6, 2.4 Hz, 1H), 7.70 (d,J = 3.4 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.9 Hz, 1H),7.44 (d, J = 8.6 Hz, 1H), 6.77 (d, J = 3.4 Hz, 1H), 4.51 (br. s., 1H),4.19-4.47 (m, 4H), 4.12 (q, J = 7.1 Hz, 2H), 3.74-3.95 (m, 2H), 3.25 (t,J = 5.6 Hz, 1H), 2.49 (br. s., 4H) MS m/z (M + H⁺) 508.0 6291-(5-Chloropyridin-2-yl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)- 1H-indole MS m/z(M + H⁺) 501.0 1180 1-(5-Chloropyridin-2-yl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR(CDCl₃) d: 8.79 (s, 1H), 8.49 (s, 1H), 8.21 (d, J = 8.6 Hz, 1H), 7.95(s, 1H), 8.00 (s, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.68 (d, J = 2.9 Hz,1H), 7.59 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 6.75 (d, J =2.9 Hz, 1H), 4.31-4.47 (m, 1H), 4.16-4.31 (m, 1H), 4.11 (q, J = 7.0 Hz,1H), 3.84-4.04 (m, 3H), 3.80 (br. s., 1H), 3.18-3.31 (m, 1H), 2.47 (br.s., 3H), 2.40 (br. s., 1H) MS m/z (M + H⁺) 507.0

Example 2

A. [4-(1-Benzhydryl-azetidin-3-yl)-piperazin-1-yl]-phenyl-methanone, 2b

The title compound 2b was prepared using the method described in Example1, substituting compound 2a for compound 1d in Procedure C. The crudecompound 2b was purified by flash column chromatography. MS m/z (M+H⁺)412.2.

B. (4-Azetidin-3-yl-piperazin-1-yl)-phenyl-methanone, 2c

The title compound 2c was prepared using the method described in Example1, substituting compound 2b for compound 1f in Procedure D. The crudecompound 2c was used in the next reaction without further purification.MS m/z (M+H⁺) 246.1.

C.1-{1-[(4-Bromophenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine,Cpd 27

The title compound 27 was prepared using the method described in Example1, substituting compound 2c for compound 1g and substituting compound 2dfor compound 1h in Procedure E. The crude compound 27 was purified byreverse phase chromatography. MS m/z (M+H⁺) 428.1/430.0.

Following the procedure described above for Example 2 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 28 1-(Phenylcarbonyl)-4-(1-{[4-(1H-pyrrol-1-yl)phenyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 415.2 291-(Phenylcarbonyl)-4-{1-[(4-pyrrolidin-1-ylphenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 419.2 30N,N-Diethyl-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline LC/MS m/z (M + H⁺) 421.2 31N,N-Dimethyl-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline MS m/z (M + H⁺) 393.2 321-{1-[(4-Phenoxyphenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 442.2 331-{1-[(4′-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 444.1 341-{1-[(4′-Methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 456.1 351-(1-{[4-(Benzyloxy)phenyl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine LC/MS (m/z) (M + H⁺) 456.1 361-{1-[(2′-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 460.2 371-Cyclohexyl-2-methyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole LC/MS m/z (M + H⁺) 486.3 381-(1-Methylethyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)-1H-benzimidazole LC/MSm/z (M + H⁺) 500.3 391-{1-[(3′,4′-Dichlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.73 (d, 1H), 7.65(m, 4H), 7.50 (m, 2H), 7.35-7.46 (m, 5H), 4.55 (m, 2H), 4.35 (m, 2H),4.01 (m, 1H), 3.80 (m, 4H), 3.17 (m, 4H); LC/MS m/z (M + H⁺) 494.1(calculated for C₂₇H₂₅Cl₂N₃O₂, 494.43) 40N-Methyl-N-phenyl-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline ¹H NMR (300 MHz, CD₃OD): δ 7.45-7.56(m, 7H), 7.41 (t, 2H), 7.22 (m, 3H), 6.80 (d, 2H), 4.27-4.75 (m, 4H),4.07 (m, 1H), 3.88 (m, 4H), 3.34 (s, 3H), 3.25 (m, 4H); LC/MS m/z (M +H⁺) 455.3 (calculated for C₂₈H₃₀N₄O₂, 454.58) 411-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]azepane ¹H NMR (300 MHz, CD₃OD): δ 7.45-7.57 (m, 7H),6.73 (d, 2H), 4.28-4.73 (m, 4H), 4.12 (m, 1H), 3.89 (m, 4H), 3.30 (m,8H), 1.80 (m, 4H), 1.54 (m, 4H); LC/MS m/z (M + H⁺) 447.3 (calculatedfor C₂₇H₃₄N₄O₂, 446.6) 425-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-propyl-1H-indole LC/MS m/z (M + H⁺) 431.1 431-(Biphenyl-4-ylcarbonyl)-2-phenyl-4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazine ¹H NMR (400 MHz, MeOD): δ 7.86-7.95(m, 1H), 7.73-7.79 (m, 1H), 7.62-7.68 (m, 2H), 7.53-7.59 (m, 2H),7.47-7.52 (m, 2H), 7.41-7.47 (m, 2H), 7.33-7.41 (m, 4H), 7.21-7.33 (m,2H), 5.67 (br. s., 1H), 4.51-4.62 (m, 2H), 4.19-4.38 (m, 1H), 4.01-4.12(m, 1H), 3.71-3.81 (m, 1H), 3.54-3.67 (m, 1H), 3.32 (m, 1H), 2.98-3.12(m, 2H), 2.79-2.90 (m, 1H), 2.44-2.56 (m, 1H); MS m/z (M + H⁺) 509.2(calculated for C₃₀H₂₈N₄O₂S, 508.65) 441-(Biphenyl-4-ylcarbonyl)-2-phenyl-4-[1-(phenylcarbonyl)azetidin-3-yl]piperazine ¹H NMR (400 MHz, MeOD): δ7.67-7.75 (m, 2H), 7.59-7.67 (m, 4H), 7.53-7.58 (m, 2H), 7.40-7.53 (m,9H), 7.31-7.40 (m, 2 H), 5.73 (br. s., 1 H), 4.34-4.57 (m, 1H),4.23-4.34 (m, 1H), 4.02-4.18 (m, 2H), 3.69-3.88 (m, 1H), 3.55-3.68 (m,1H), 3.35-3.46 (m, 2H), 3.07 (m, 1H), 2.81-2.93 (m, 1H), 2.43-2.63 (m,1H); MS m/z (M⁺) 502.2 (calculated for C₃₃H₃₁N₃O₂, 502.23) 451-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-methyl-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 447.29 (calculated forC₂₅H₂₆N₄O₂S, 446.58) 462-Methyl-1-{1-[(4-phenoxyphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 463.2 (calculatedfor C₂₅H₂₆N₄O₃S, 462.57) 471-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-2-methyl-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 461.0 (calculated forC₂₆H₂₈N₄O₂S, 460.60) 481-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]-1H-benzimidazole MS m/z (M + H⁺) 466.3 (calculatedfor C₂₈H₂₇N₅O₂, 465.56) 491-{1-[(4-Fluorophenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 368.2 (calculated forC₂₁H₂₂FN₃O₂, 367.43) 50N-Benzyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-thiazol-2-amine MS m/z (M + H⁺) 462.2 (calculated forC₂₅H₂₇N₅O₂S, 461.59) 519-Methyl-3-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-9H-carbazole MS m/z (M + H⁺) 453.3 (calculated forC₂₈H₂₈N₄O₂, 452.56) 52N-Benzyl-2-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline MS m/z (M + H⁺) 455.3 (calculated for C₂₈H₃₀N₄O₂,454.58) 53 1-(Phenylcarbonyl)-4-{1-[(4-piperidin-1-ylphenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 433.3(calculated for C₂₆H₃₂N₄O₂, 432.57) 54N-Butyl-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline MS m/z (M + H⁺) 421.2 (calculated for C₂₅H₃₂N₄O₂,420.56) 55 6-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3,4,9-tetrahydro-1H-carbazole MS (m/z) (M + H⁺) 443.3(calculated for C₂₇H₃₀N₄O₂, 442.57) 562-[3-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]-2,3-dihydro-1H-isoindole MS m/z (M + H⁺) 467.2(calculated for C₂₉H₃₀N₄O₂, 466.59) 572-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-N-[3-(trifluoromethyl)phenyl]aniline MS m/z (M + H⁺) 509.1(calculated for C₂₈H₂₇F₃N₄O₂, 508.55) 58N-Phenyl-2-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline MS m/z (M + H⁺) 441.2 (calculated for C₂₇H₂₈N₄O₂,440.55) 59 N-(3-Fluorophenyl)-2-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline MS m/z (M + H⁺) 459.2 (calculated forC₂₇H₂₇FN₄O₂, 458.54) 602,3-Dimethyl-N-[2-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]aniline MS m/z (M + H⁺) 469.2(calculated for C₂₉H₃₂N₄O₂, 468.60) 4611-(1-{[2-(Benzyloxy)phenyl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 456.221 4621-{1-[(3-Phenoxyphenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 442.3 4631-{1-[(2-Phenoxyphenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 442.3 4641-(Phenylcarbonyl)-4-(1-{[4-(trifluoromethoxy)phenyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M +H⁺) 434.161 4651-{1-[(3-Bromo-4-methoxyphenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 458.1 4661-{1-[(3-Chloro-4-methoxyphenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 414.151 4671-{1-[(4-Ethoxyphenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 394.205 4681-{1-[(3-Iodo-4-methoxyphenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 506.086 4691-(1-{[4-(1-Methylethoxy)phenyl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 408.221 4701-(1-{[4-(Methylsulfanyl)phenyl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 396.167 4714-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl acetate MS m/z (M + H⁺) 415.136 4721-(1-{[4-(Methylsulfonyl)phenyl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 428.157 539N-[3-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]cyclohexanecarboxamide MS m/z (M + H⁺) 475.2 6221-(Phenylcarbonyl)-4-[1-({4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}carbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 484.0 531N-Benzyl-3-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline MS m/z (M + H⁺) 455.1 5651-Benzyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)pyridin-2(1H)-one MS m/z (M + H⁺) 457.1 5621-(3-Chlorobenzyl)-3-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)pyridin-2(1H)-one MS m/z (M + H⁺) 491.1 6271-(Phenylcarbonyl)-4-(1-{[3-(1H-pyrrol-1-yl)phenyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 415.2 5414-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]morpholine MS m/z (M + H⁺) 435.1 14854-[5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)pyridin-2-yl]morpholine MS m/z (M + H⁺) 436.0 5594-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-2-phenyl-1-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 516.1 6284-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-phenyl-1-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 502.0 14044-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-phenyl-1-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 509.1 14644-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-2-phenyl-1-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 523.1 12662-Benzyl-1-(biphenyl-4-ylcarbonyl)-4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 523.3 12842-Benzyl-1-(biphenyl-4-ylcarbonyl)-4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 523.2 954(2R,6S)-2,6-Dimethyl-1-(1,3-thiazol-2-ylcarbonyl)-4-(1-{[6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 509.0

Example 3

A. (4-Benzyl-phenyl)-piperazin-1-yl-methanone, 3b

To a solution of compound 1a (1 g, 5.36 mmol), compound 3a (1.14 g, 5.36mmol), and DIPEA (1.38 g, 10.7 mmol) in acetonitrile (20 mL) was addedHBTU (2.64 g, 7.0 mmol). The reaction was stirred for 18 h at which timethe solvent was removed under reduced pressure and the crude productpurified by reverse phase HPLC. Upon lyophilization, the remaining solidwas dissolved in DCM (20 mL) and trifluoroacetic acid was slowly added(15 mL). After stirring at room temperature 2 h, the solvents wereremoved and the residue partitioned between aqueous 1N NaOH and CHCl₃.The organic layer was separated, dried (MgSO₄), filtered, and thenconcentrated to yield compound 3b (1.21 g).

B.[4-(1-Benzhydryl-azetidin-3-yl)-piperazin-1-yl]-4-benzyl-phenyl-methanone,3c

The title compound 3c was prepared using the method described in Example1, substituting compound 3b for compound 1d in Procedure C.

C. (4-Azetidin-3-yl-piperazin-1-yl)-4-benzyl-phenyl-methanone, 3d

The title compound 3d was prepared using the method described in Example1, substituting compound 3c for compound 1f in Procedure D.

D.1-[(4-Benzylphenyl)carbonyl]-4-[1-(phenylcarbonyl)azetidin-3-yl]piperazine,Cpd 61

Compound 3d was converted into title compound 61 using the methoddescribed in Example 2, substituting compound 3d for compound 2c,benzoic acid (compound 1k) for compound 2d, and HBTU for HATU inProcedure D. ¹H NMR (400 MHz, MeOD): δ 7.64 (d, J=1.7 Hz, 2H), 7.51-7.58(m, 1H), 7.48 (br. s., 2H), 7.38 (s, 2H), 7.33 (d, J=8.1 Hz, 2H), 7.25(br. s., 2H), 7.20 (d, J=7.3 Hz, 3H), 4.51-4.64 (m, 1H), 4.33-4.51 (m,2H), 4.20-4.33 (m, 1H), 4.01 (s, 2H), 3.86-3.96 (m, 2H), 3.69-3.86 (m,3H), 3.07 (br. s., 4H); MS m/z (M+H⁺) 440.2 (calculated for C₂₈H₂₉N₃O₂,439.56)

Following the procedure described above for Example 3 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 12461-(Biphenyl-4-ylcarbonyl)-4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 433.1 12351-(Biphenyl-4-ylcarbonyl)-4-[1-(isothiazol-5-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 433.2 12421-(Biphenyl-4-ylcarbonyl)-4-{1-[(3-fluorophenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 444.11236 1-(Biphenyl-4-ylcarbonyl)-4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 433.2 13831-(Biphenyl-4-ylcarbonyl)-4-[1-(1H-pyrrol-2-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 414.0 12761-(Biphenyl-4-ylcarbonyl)-4-[1-(1,2,3-thiadiazol-4-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 434.0 12921-(Biphenyl-4-ylcarbonyl)-4-[1-(1H-pyrrol-3-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 413.0 14002-({3-[4-(Biphenyl-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)pyrimidine MS m/z (M + H⁺) 428.1 12831-(Biphenyl-4-ylcarbonyl)-4-[1-(1,3-oxazol-2-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 417.0 6761-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]-4-{[5-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}piperazine MS m/z (M +H⁺) 481.1 722 1-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-yl]-4-{[5-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}piperazine MS m/z (M +H⁺) 462.1 741 1-[1-(1H-Pyrrol-3-ylcarbonyl)azetidin-3-yl]-4-{[5-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}piperazine MS m/z (M +H⁺) 461.0 716 1-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]-4-{[5-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}piperazine MS m/z (M +H⁺) 481.0 703 1-[1-(Isothiazol-5-ylcarbonyl)azetidin-3-yl]-4-{[5-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}piperazine MS m/z (M +H⁺) 481.0 921 1-[1-(1,2,5-Oxadiazol-3-ylcarbonyl)azetidin-3-yl]-4-{[5-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}piperazine MS m/z (M +H⁺) 466.1 753 1-[1-(1,2,3-Thiadiazol-4-ylcarbonyl)azetidin-3-yl]-4-{[5-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}piperazine MS m/z (M +H⁺) 482.2 1067 1-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]-4-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}piperazine MS m/z (M + H⁺) 501.01243 1-[1-(1H-Pyrrol-3-ylcarbonyl)azetidin-3-yl]-4-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}piperazine MS m/z (M + H⁺) 483.01166 1-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-yl]-4-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}piperazine MS m/z (M + H⁺) 483.01402 4-(Biphenyl-4-ylcarbonyl)-2-phenyl-1-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 509.0 14014-(Biphenyl-4-ylcarbonyl)-2-phenyl-1-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 509.0

Example 4

A. 3-(4-Benzoyl-piperazin-1-yl)-azetidine-1-carboxylic acid tert-butylester, 4b

To a solution of 1-Boc-azetidin-3-one (compound 4a) and compound 2a inCH₃OH was added decaborane at room temperature. The reaction mixture wasstirred at room temperature for 18 h. The solvent was removed underreduced pressure, and the crude compound 4b was used in the subsequentreaction without further purification. MS m/z (M+H⁺) 346.2.

B. (4-Azetidin-3-yl-piperazin-1-yl)-phenyl-methanone, 2c

The title compound 2c was prepared using the method described in Example1, substituting compound 4b for compound 1c in Procedure B. The crudecompound 2c was used in the next reaction without further purification.MS m/z (M+H⁺) 246.1.

C.1-{1-[(4-Methyl-2-phenyl-1,3-thiazol-5-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine,Cpd 62

The title compound 62 was prepared using the method described in Example1, substituting compound 2c for compound 1g and substituting compound 4cfor compound 1h in Procedure E. The crude compound 62 was purified byreverse phase chromatography. MS m/z (M+H⁺) 447.1.

Following the procedure described above for Example 4 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 63 1-{1-[(4-Methyl-2-thiophen-2-yl-1,3-thiazol-5-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M +H⁺) 453.1 64 1-(1-{[4-Methyl-2-(4-methylphenyl)-1,3-thiazol-5-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine LC/MS m/z (M +H⁺) 461.2 651-[1-({4-Methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine LC/MS m/z (M +H⁺) 515.1 66 1-(Phenylcarbonyl)-4-{1-[(3-thiophen-2-ylphenyl)carbonyl]azetidin-3-yl}piperazine LC/MS m/z (M + H⁺) 432.1 671-(Phenylcarbonyl)-4-{1-[(4-thiophen-2-ylphenyl)carbonyl]azetidin-3-yl}piperazine LC/MS m/z (M + H⁺) 432.1 681-(Phenylcarbonyl)-4-{1-[(3-pyridin-2-ylphenyl)carbonyl]azetidin-3-yl}piperazine LC/MS m/z (M + H⁺) 427.2 691-(Phenylcarbonyl)-4-{1-[(3-pyridin-3-ylphenyl)carbonyl]azetidin-3-yl}piperazine LC/MS m/z (M + H⁺) 427.2 701-(Phenylcarbonyl)-4-{1-[(3-pyridin-4-ylphenyl)carbonyl]azetidin-3-yl}piperazine LC/MS m/z (M + H⁺) 427.2 711-(Phenylcarbonyl)-4-{1-[(4-pyridin-3-ylphenyl)carbonyl]azetidin-3-yl}piperazine LC/MS m/z (M + H⁺) 427.2 721-(Phenylcarbonyl)-4-(1-{[2′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.81 (d,1H), 7.64-7.77 (m, 3H), 7.59 (t, 1H), 7.42-7.54 (m, 7H), 7.36 (d, 1H),4.70 (m, 1H), 4.58 (m, 1H), 4.47 (m, 1H), 4.35 (m, 1H), 4.04 (m, 1H),3.86 (m, 4H), 3.19 (m, 4H); LC/MS m/z (M + H⁺) 494.2 (calculated forC₂₈H₂₆F₃N₃O₂, 493.53) 731-(Phenylcarbonyl)-4-(1-{[2′-(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3-yl)piperazine LC/MS m/z (M + H⁺) 494.2 741-(Phenylcarbonyl)-4-(1-{[4′-(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3-yl)piperazine LC/MS m/z (M + H⁺) 494.2 751-(Phenylcarbonyl)-4-(1-{[4′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (300 MHz, CD₃OD): δ7.74-7.89 (m, 8H), 7.46-7.54 (m, 5H), 4.68 (m, 1H), 4.61 (m, 1H), 4.47(m, 1H), 4.38 (m, 1H), 4.07 (m, 1H), 3.88 (m, 4H), 3.23 (m, 4H)); LC/MSm/z (M + H⁺) 494.2 (calculated for C₂₈H₂₆F₃N₃O₂, 493.53) 764′-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-carbonitrile LC/MS m/z (M + H⁺) 451.0 771-{1-[(3′-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, DMSO-d₆): δ 7.77-7.86 (m,3H), 7.68-7.76 (m, 3H), 7.43-7.58 (m, 7H), 4.60 (m, 2H), 4.39 (m, 1H),4.28 (m, 1H), 4.08 (m, 1H), 3.29-3.94 (m, 6H), 3.06 (m, 2H); LC/MS m/z(M + H⁺) 460.0 (calculated for C₂₇H₂₆ClN₃O₂, 459.98) 781-{1-[(4′-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 460.0 791-{1-[(3′,5′-Dichlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, DMSO-d₆): δ 7.87 (d, 2H),7.81 (d, 2H), 7.73 (d, 2H), 7.67 (t, 1H), 7.48 (m, 5H), 4.67 (m, 1H),4.58 (t, 1H), 4.43 (m, 1H), 4.29 (t, 1H), 4.10 (m, 1H), 3.25-3.93 (m,6H), 3.06 (m, 2H); LC/MS m/z (M + H⁺) 494.1 (calculated forC₂₇H₂₅Cl₂N₃O₂, 494.43) 80 1-(Phenylcarbonyl)-4-{1-[(5-phenylpyridin-3-yl)carbonyl]azetidin-3-yl}piperazine LC/MS m/z (M + H⁺) 427.2 811-{1-[(2-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 444.1 824′-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-4-carbonitrile LC/MS m/z (M + H⁺) 451.2 831-{1-[(4′-Bromobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.25-7.74 (m,13H), 4.08-4.59 (m, 4H), 3.43-3.97 (m, 5H), 2.92 (m, 4H); LC/MS m/z (M +H⁺) 504.0/506.1 (calculated for C₂₇H₂₆BrN₃O₂, 504.43) 4741-(1-{[2-(4-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 477.2 4731-{1-[3-(4-Methylphenyl)propanoyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 392.3 841-{1-[3-(4-Chlorophenyl)propanoyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 412.21 (calculated forC₂₃H₂₆ClN₃O₂, 411.92) 851-{1-[3-(4-Bromophenyl)propanoyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 456.15 (calculated forC₂₃H₂₆BrN₃O₂, 456.38) 86 1-(Phenylcarbonyl)-4-(1-{3-[4-(trifluoromethyl)phenyl]propanoyl}azetidin-3-yl)piperazine LC/MS m/z(M + H⁺) 446.23 (calculated for C₂₄H₂₆F₃N₃O₂, 445.48) 871-{1-[3-(3-Chlorophenyl)propanoyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 412.18 (calculated forC₂₃H₂₆ClN₃O₂, 411.92) 881-{1-[3-(2-Chlorophenyl)propanoyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 412.21 (calculated forC₂₃H₂₆ClN₃O₂, 411.92) 891-{1-[3-(2,6-Dichlorophenyl)propanoyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 446.16 (calculated forC₂₃H₂₅Cl₂N₃O₂, 446.37) 901-{1-[3-(1,3-Benzodioxol-5-yl)propanoyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 422.2 (calculated forC₂₄H₂₇N₃O₄, 421.49) 91 1-(Phenylcarbonyl)-4-{1-[(2E)-3-{4-[(trifluoromethyl)sulfanyl]phenyl}prop-2-enoyl]azetidin-3- yl}piperazineLC/MS m/z (M + H⁺) 476.20 (calculated for C₂₄H₂₄F₃N₃O₂S, 475.54 921-(1-{3-[3,5-Bis(trifluoromethyl)phenyl]propanoyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 514.18(calculated for C₂₅H₂₅F₆N₃O₂, 514.18) 931-[1-(3-Naphthalen-1-ylpropanoyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 428.27 (calculated forC₂₇H₂₉N₃O₂, 427.54) 941-{1-[3-(3,4-Dichlorophenyl)propanoyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 448.16 (calculated forC₂₃H₂₅Cl₂N₃O₂, 446.38) 951-{1-[3-(4-Phenoxyphenyl)propanoyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 470.29 (calculated forC₂₉H₃₁N₃O₃, 469.59) 96 1-{1-[(4-Chlorophenoxy)acetyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 414.21 (calculated forC₂₂H₂₄ClN₃O₃, 413.91) 971-(Phenylcarbonyl)-4-{1-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)propanoyl]azetidin-3- yl}piperazine. LC/MS m/z(M + H⁺) 488.32 (calculated for C₃₁H₄₁N₃O₂, 487.69) 981-{1-[3-(2-Bromophenyl)propanoyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 458.18 (calculated forC₂₃H₂₆BrN₃O₂, 456.39 99 1-(Phenylcarbonyl)-4-(1-{[4-(trifluoromethoxy)phenoxy]acetyl}azetidin-3-yl)piperazine. LC/MS m/z(M + H⁺) 464.26 (calculated for C₂₃H₂₄F₃N₃O₄, 475.54 100N-Cyclopropyl-4-(3-oxo-3-{3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}propyl)benzenesulfonamide. LC/MS m/z (M + H⁺) 497.23(calculated for C₂₆H₃₂N₄O₄S, 496.21 101N-(Cyclohexylmethyl)-N-methyl-4-(3-oxo-3-{3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}propyl)aniline. LC/MS m/z(M + H⁺) 503.37 (calculated for C₃₁H₄₂N₄O₂, 502.71 1021-[1-(1-Benzothiophen-2-ylcarbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 406.2 (calculated forC₂₃H₂₃N₃O₂S, 405.52 1031-{1-[(2E)-3-(2-Chlorophenyl)prop-2-enoyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 410.29 (calculated forC₂₃H₂₄ClN₃O₂, 409.92 1041-{1-[(2E)-3-(2-Bromophenyl)prop-2-enoyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 456.16 (calculated forC₂₃H₂₄BrN₃O₂, 454.37 1051-{1-[(2E)-3-Naphthalen-2-ylprop-2-enoyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 426.32 (calculated forC₂₇H₂₇N₃O₂, 425.54 106 1-(Phenylcarbonyl)-4-{1-[(4-phenylcyclohexyl)carbonyl]azetidin-3-yl}piperazine. LC/MS m/z (M + H⁺)432.38 (calculated for C₂₇H₃₃N₃O₂, 431.58 1073-Methyl-2-phenyl-8-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4H-chromen-4-one. LC/MS m/z (M + H⁺) 508.31(calculated for C₃₁H₂₉N₃O₄, 507.59 108Phenyl[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)cyclohexyl]methanone. LC/MS m/z (M + H⁺) 460.35 (calculatedfor C₂₈H₃₃N₃O₃, 459.59) 109 tert-Butyl4-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]piperidine-1-carboxylate. ¹H NMR (300MHz, MeOD): δ 7.55 (Ar, 2H), 7.4 (m, 5H). 7.25 (ar, 2H), 4.5 (m, 2H),4.3 (m, 2H), 4.1 (m, 3H), 3.7 (bm, 4H), 3.0 (bm, 4H), 2.7 (m, 4H), 1.7(m, 2H), 1.5 (m, 2H), 1.4 (s, 9H). LC/MS m/z (M + H⁺) 533.33 (calculatedfor C₃₁H₄₀N₄O₄, 532.69 1101-{1-[(2-Phenoxypyridin-3-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 443.28 (calculated forC₂₆H₂₆N₄O₃, 442.52 111 tert-Butyl3-[2-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]pyrrolidine-1-carboxylate. LC/MS m/z(M + H⁺) 519.35 (calculated for C₃₀H₃₈N₄O₄, 518.66) 496 tert-Butyl[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]carbamate ¹H NMR (400 MHz, CDCl₃): δ 7.57 (d, J =8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.36-7.42 (m, 4H), 7.20 (s, 1H),4.25-4.34 (m, 1H), 4.17-4.26 (m, 1H), 4.13 (s, 1H), 3.97-4.08 (m, 1H),3.81-3.95 (m, 1H), 3.68-3.80 (m, 1H), 3.32-3.61 (m, 2H), 3.15-3.27 (m,1H), 2.16-2.59 (m, 4H), 1.50 (s, 9H) MS (m/z) (M + H⁺) 465.2 6191-(1-{[2-(4-Chlorophenyl)-4-methyl-1,3-thiazol-5-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺)481.0 618 1-[1-({4-Methyl-2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺)515.1 620 1-(1-{[2-(3-Chlorophenyl)-4-methyl-1,3-thiazol-5-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺)481.0 621 1-(1-{[2-(4-Fluorophenyl)-4-methyl-1,3-thiazol-5-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺)465.1 625 1-(Phenylcarbonyl)-4-(1-{[2-phenyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 485.1 6231-{1-[(2-Methyl-5-phenylfuran-3-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 430.2 6241-(Phenylcarbonyl)-4-(1-{[5-phenyl-2-(trifluoromethyl)furan-3-yl]carbonyl}azetidin-3-yl)piperazine MS m/z(M + H⁺) 484.0 5581-[1-({2-[(4-Chlorophenoxy)methyl]-4-methyl-1,3-thiazol-5-yl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺)511.1 626 1-(Phenylcarbonyl)-4-(1-{[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 484.2

Example 5

A. 4-(1-Benzhydryl-azetidin-3-yl)-piperazine-1-carboxylic acidtert-butyl ester, 5a

The title compound 5a was prepared using the method described in Example1, substituting compound 1a for compound 1d in Procedure C. The crudecompound 5a was used in the next reaction without further purification.MS m/z (M+H⁺) 408.1.

B. 1-(1-Benzhydryl-azetidin-3-yl)-piperazine, 5b

The title compound 5b was prepared using the method described in Example1, substituting compound 5a for compound 1c in Procedure B. The crudecompound 5b was used in the next reaction without further purification.MS m/z (M+H⁺) 208.1.

C.[4-(1-Benzhydryl-azetidin-3-yl)-piperazin-1-yl]-thiazol-2-yl-methanone,5d

The title compound 5d was prepared using the method described in Example1, substituting compound 5b for compound 1g and substituting compound 5cfor compound 1h in Procedure E. The crude compound 5d was purified byflash column chromatography. MS m/z (M+H⁺) 419.2.

D. (4-Azetidin-3-yl-piperazin-1-yl)-thiazol-2-yl-methanone, 5e

The title compound 5e was prepared using the method described in Example1, substituting compound 5d for compound 1f in Procedure D. The crudecompound 5e was used in the next reaction without further purification.MS m/z (M+H⁺) 253.2.

E.1-{1-[(4-Methyl-2-phenyl-1,3-thiazol-5-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 133

The title compound 133 was prepared using the method described inExample 1, substituting compound 5e for compound 1g and substitutingcompound 4c for compound 1h in Procedure E. The crude compound 133 waspurified by reverse phase chromatography. ¹H NMR (300 MHz, CD₃OD): δ7.98 (m, 3H), 7.89 (d, 1H), 7.46-7.55 (m, 3H), 4.80 (m, 1H), 4.41-4.69(m, 4H), 4.09 (m, 3H), 3.35 (m, 5H), 2.68 (s, 3H); LC/MS m/z (M+H⁺)454.2 (calculated for C₂₂H₂₃N₅O₂S₂, 453.59).

Following the procedure described above for Example 5 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 134 1-{1-[(4-Methyl-2-thiophen-2-yl-1,3-thiazol-5-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 7.98 (s, 1H), 7.88 (s, 1H), 7.67 (m, 2H), 7.16(m, 1H), 4.79 (m, 1H), 4.35-4.69 (m, 4H), 4.07 (m, 3H), 3.33 (m, 5H),2.62 (s, 3H); LC/MS m/z (M + H⁺) 460.0 (calculated for C₂₀H₂₁N₅O₂S₃,459.61) 135 1-(1-{[4-Methyl-2-(4-methylphenyl)-1,3-thiazol-5-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 7.98 (d, 1H), 7.82-7.91 (m, 3H), 7.32 (d, 2H),4.80 (m, 1H), 4.40-4.66 (m, 4H), 4.08 (m, 3H), 3.34 (m, 5H), 2.66 (s,3H), 2.46 (s, 3H); LC/MS m/z (M + H⁺) 468.1 (calculated forC₂₃H₂₅N₅O₂S₂, 467.62) 1361-[1-({4-Methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 8.19 (d, 2H), 7.97 (d, 1H), 7.86 (d, 1H), 7.82(d, 2H), 4.25-4.76 (m, 5H), 3.95 (m, 2H), 3.76 (m, 1H), 3.33 (m, 2H),2.99 (m, 3H), 2.69 (s, 3H); LC/MS m/z (M + H⁺) 522.2 (calculated forC₂₃H₂₂F₃N₅O₂S₂, 521.59) 1371-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(3-thiophen-2-ylphenyl)carbonyl]azetidin-3-yl}piperazine ¹H NMR (300 MHz, CD₃OD): δ7.97 (d, 1H), 7.91 (t, 1H), 7.88 (d, 1H), 7.83 (dt, 1H), 7.54 (m, 2H),7.47 (dd, 2H), 7.13 (dd, 1H), 4.30-4.79 (m, 5H), 4.02 (m, 3H), 3.24 (m,5H); LC/MS m/z (M + H⁺) 439.0 (calculated for C₂₂H₂₂N₄O₂S₂, 438.57) 1381-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-thiophen-2-ylphenyl)carbonyl]azetidin-3-yl}piperazine ¹H NMR (300 MHz, CD₃OD): δ7.97 (d, 1H), 7.89 (d, 1H), 7.75 (m, 4H), 7.51 (m, 2H), 7.14 (m, 1H),4.28-4.82 (m, 5H), 4.02 (m, 3H), 3.25 (m, 5H); LC/MS m/z (M + H⁺) 439.1(calculated for C₂₂H₂₂N₄O₂S₂, 438.57) 1391-{1-[(3-Pyridin-2-ylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 434.0 1401-{1-[(3-Pyridin-3-ylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 434.0 1411-{1-[(3-Pyridin-4-ylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 434.0 1421-{1-[(4-Pyridin-3-ylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 434.0 1435-[3-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]pyrimidine LC/MS m/z (M + H⁺) 435.0 1445-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]pyrimidine LC/MS m/z (M + H⁺) 435.0 1452-[3-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]pyrimidine LC/MS m/z (M + H⁺) 435.0 1462-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]pyrimidine LC/MS m/z (M + H⁺) 435.0 1471-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[2′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine ¹H NMR(300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.88 (d, 1H), 7.81 (d, 1H), 7.74 (d,2H), 7.68 (t, 1H), 7.59 (t, 1H), 7.45 (d, 2H), 7.37 (d, 1H), 4.33-4.82(m, 5H), 4.04 (m, 3H), 3.27 (m, 5H); LC/MS m/z (M + H⁺) 501.0(calculated for C₂₅H₂₃F₃N₄O₂S, 500.55) 1481-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[2′-(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3- yl)piperazine ¹H NMR(300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.88 (d, 1H), 7.81 (d, 1H), 7.73 (dt,1H), 7.67 (d, 1H), 7.49-7.64 (m, 4H), 7.39 (d, 1H), 4.30-4.81 (m, 5H),4.03 (m, 3H), 3.25 (m, 5H); LC/MS m/z (M + H⁺) 501.0 (calculated forC₂₅H₂₃F₃N₄O₂S, 500.55) 149 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4′-(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3- yl)piperazine LC/MSm/z (M + H⁺) 501.0 150 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine ¹H NMR(300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.76-7.89 (m, 9H), 4.62-4.77 (m, 5H),3.97 (m, 3H), 3.13 (m, 5H); LC/MS m/z (M + H⁺) 501.0 (calculated forC₂₅H₂₃F₃N₄O₂S, 500.55) 1511-(1-{[3-(6-Bromopyridin-2-yl)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 8.34(t, 1H), 8.21 (dt, 1H), 7.97 (d, 1H), 7.94 (dd, 1H), 7.87 (d, 1H),7.72-7.82 (m, 2H), 7.54-7.67 (m, 2H), 4.26-4.68 (m, 6H), 3.84-4.06 (m,3H), 3.13 (m, 4H); LC/MS m/z (M + H⁺) 512.0/513.9 (calculated forC₂₃H₂₂BrN₅O₂S, 512.43) 1521-(1-{[3-(5-Nitropyridin-2-yl)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 479.0 1531-(1-{[4-(5-Nitropyridin-2-yl)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 479.0 1541-(1-{[5-(4-Fluorophenyl)pyridin-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 452.0 1551-(1-{[2-(4-Fluorophenyl)-1,3-thiazol-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 458.0 1561-(1-{[2-(3-Fluorophenyl)-1,3-thiazol-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 458.0 1571-(1-{[2-(2,4-Dichlorophenyl)-1,3-thiazol-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine LC/MSm/z (M + H⁺) 507.9 158 1-(1-{[2-(3,5-Dichlorophenyl)-1,3-thiazol-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 8.31 (s, 1H), 7.89 (m, 3H), 7.79 (d, 1H), 7.52(t, 1H), 5.01 (m, 1H), 4.84 (m, 2H), 4.65 (m, 1H), 4.38 (dd, 1H), 4.26(dd, 1H), 3.93 (m, 3H), 3.17 (m, 4H); LC/MS m/z (M + H⁺) 507.9(calculated for C₂₁H₁₉Cl₂N₅O₂S₂, 508.45) 1591-(1-{[2-(4-Methoxyphenyl)-1,3-thiazol-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 470.0160 1-{1-[(2-Phenyl-1,3-thiazol-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 440.0 1614′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-carbonitrile ¹H NMR (300 MHz, DMSO-d₆): δ 8.10(d, 1H), 8.06 (d, 1H), 7.78-7.86 (m, 3H), 7.68-7.77 (m, 3H), 7.46-7.58(m, 2H), 4.62 (m, 2H), 4.40 (m, 1H), 4.30 (m, 1H), 4.08 (m, 1H),4.27-3.87 (m, 6H), 3.12 (m, 2H); LC/MS m/z (M + H⁺) 458.1 (calculatedfor C₂₅H₂₃N₅O₂S, 457.56) 1621-{1-[(3′-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, DMSO-d₆): δ 8.10 (d,1H), 8.06 (d, 1H), 7.78-7.86 (m, 3H), 7.68-7.77 (m, 3H), 7.46-7.58 (m,2H), 4.61 (m, 2H), 4.37 (m, 1H), 4.29 (m, 1H), 4.05 (m, 1H), 4.30-3.84(m, 6H), 3.08 (m, 2H); LC/MS m/z (M + H⁺) 467.1 (calculated forC₂₄H₂₃ClN₄O₂S, 466.99) 1631-{1-[(4′-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.98 (d, 1H),7.88 (d, 1H), 7.76 (m, 4H), 7.66 (m, 2H), 7.48 (m, 2H), 4.71 (m, 3H),4.58 (m, 1H), 4.47 (m, 1H), 4.36 (m, 1H), 4.02 (m, 3H), 3.23 (m, 4H);LC/MS m/z (M + H⁺) 467.1 (calculated for C₂₄H₂₃ClN₄O₂S, 466.99) 1641-{1-[(3′,5′-Dichlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.88 (d,1H), 7.78 (d, 1H), 7.68 (m, 4H), 7.55 (d, 2H), 7.39 (t, 1H), 4.57 (m,3H), 4.45 (m, 1H), 4.35 (m, 1H), 4.23 (m, 1H), 3.91 (m, 2H), 3.81 (m,1H), 3.03 (m, 4H); LC/MS m/z (M + H⁺) 501.0 (calculated forC₂₄H₂₂Cl₂N₄O₂S, 501.44) 1651-{1-[(5-Phenylpyridin-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 434.1 1661-{1-[(2-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H),7.87 (d, 1H), 7.37-7.67 (m, 8H), 4.66 (m, 3H), 4.53 (m, 1H), 4.42 (m,1H), 4.30 (m, 1H), 3.98 (m, 2H), 3.85 (m, 1H), 3.07 (m, 4H); LC/MS m/z(M + H⁺) 451.0 (calculated for C₂₄H₂₃FN₄O₂S, 450.54) 1674′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-4-carbonitrile ¹H NMR (300 MHz, CD₃OD): δ 7.98 (d,1H), 7.77-7.92 (m, 9 H), 4.63-4.79 (m, 3H), 4.57 (m, 1H), 4.46 (m, 1H),4.35 (m, 1H), 3.90-4.13 (m, 3 H), 3.19 (m, 4 H); LC/MS m/z (M + H⁺)458.1 (calculated for C₂₅H₂₃N₅O₂S, 457.56) 1681-{1-[(4′-Bromobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H),7.87 (d, 1H), 7.76 (m, 4H), 7.62 (dd, 4H), 4.67 (m, 3H), 4.51 (m, 1H),4.44 (m, 1H), 4.30 (m, 1H), 3.98 (m, 2H), 3.88 (m, 1H), 3.10 (m, 4H);LC/MS m/z (M + H⁺) 511.0/513.0 (calculated for C₂₄H₂₃BrN₄O₂S, 511.44)169 1-{1-[(5-Phenylpyridin-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 434.1 1701-{1-[(2-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H),8.22 (s, 1H), 7.37-7.67 (m, 8H), 4.70 (m, 1H), 4.57 (m, 1H), 4.45 (m,1H), 4.34 (m, 1H), 4.11 (m, 4H), 3.99 (m, 1H), 3.17 (m, 4H); LC/MS m/z(M + H⁺) 451.0 (calculated for C₂₄H₂₃FN₄O₂S, 450.54) 1714′-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-4-carbonitrile LC/MS m/z (M + H⁺) 458.1 1721-{1-[(4′-Bromobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H),8.22 (s, 1H), 7.76 (m, 4H), 7.61 (dd, 4H), 4.68 (m, 1H), 4.57 (m, 1H),4.46 (m, 1H), 4.36 (m, 1H), 4.15 (m, 4H), 4.04 (m, 1H), 3.22 (m, 4H);LC/MS m/z (M + H⁺) 511.0/513.0 (calculated for C₂₄H₂₃BrN₄O₂S, 511.44)475 1-{1-[(4-Phenylcyclohexyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 439.2 4763-Methyl-2-phenyl-8-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4H-chromen-4-one MS m/z (M + H⁺) 515.2 4771-[1-(3-Phenylprop-2-ynoyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 381.1 478Phenyl-[4-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)cyclohexyl]methanone MS m/z (M + H⁺) 467.2 4791-[1-({2-[(4-Methylphenyl)sulfanyl]pyridin-3-yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 480.1 2981-(1-{[5-(4-Methylphenyl)-1H-pyrrol-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 436.2 1122-Methyl-4-{1-[(4-phenoxyphenyl)carbonyl]azetidin-3-yl}-1-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 463.2 (calculatedfor C₂₅H₂₆N₄O₃S, 462.57) 1132-Methyl-4-{1-[(3-phenoxyphenyl)carbonyl]azetidin-3-yl}-1-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 463.2 (calculatedfor C₂₅H₂₆N₄O₃S, 462.57) 1141-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-phenyl-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 509.0 (calculated forC₃₀H₂₈N₄O₂S, 508.65) 1154-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-2-methyl-1-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 461.0 (calculated forC₂₆H₂₈N₄O₂S, 460.60) 1164-[1-(Biphenyl-3-ylcarbonyl)azetidin-3-yl]-2-methyl-1-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 446.9 (calculated forC₂₅H₂₆N₄O₂S, 446.58) 1174-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-methyl-1-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H+) 447.3 (calculated forC₂₅H₂₆N₄O₂S, 446.58) 4891-(1-{[2-(4-Chlorophenyl)-4-methyl-1,3-thiazol-5-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 7.81-8.02 (m, 4H), 7.52 (d, 2H), 4.30-4.64 (m,6H) 3.84-4.09 (m, 3H), 3.10-3.29 (m, 4H), 2.67 (s, 3H); LC/MS m/z (M +H⁺) 488.1 (calculated for C₂₂H₂₂ClN₅O₂S₂, 488.03) 4901-(1-{[2-(3-Chlorophenyl)-4-methyl-1,3-thiazol-5-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 7.95-8.05 (m, 2H), 7.84-7.94 (m, 2H), 7.45-7.60(m, 2H), 4.32-4.84 (m, 6H) 3.92-4.09 (m, 3H), 3.15-3.27 (m, 4H), 2.68(s, 3H); LC/MS m/z (M + H⁺) 488.1 (calculated for C₂₂H₂₂ClN₅O₂S₂,488.03) 485 1-[1-({4-Methyl-2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.16-8.36 (m, 3H), 7.79-7.89 (m,1H), 7.66-7.78 (m, 1H), 4.23-4.76 (m, 4H) 3.84-4.22 (m, 5H), 3.04-3.22(m, 4H), 2.70 (s, 3H); LC/MS m/z (M + H⁺) 522.2 (calculated forC₂₃H₂₂F₂N₅O₂S₂, 521.59) 7442,3-Dimethyl-N-[2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]aniline MS m/z (M + H⁺) 476.1 12971-{1-[(1,5-Diphenyl-1H-pyrazol-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 499.1 7682-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-N-[3-(trifluoromethyl)phenyl]aniline MS m/z (M + H⁺) 516.2781 N-Phenyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline MS m/z (M + H⁺) 448.0 1460N-(3-Bromophenyl)-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)benzamide MS m/z (M +H⁺) 552.0/554.0 12141-(1-{[5-Methyl-2-(4-methylphenyl)-2H-1,2,3-triazol-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 452.1 754 N-(3-Fluorophenyl)-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline MS m/z (M + H⁺)466.0 1103 1-(1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 615.0 8861-[1-(Phenoxathiin-2-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 479.1 13011-(1-{[1-(4-Fluorophenyl)-3,5-dimethyl-1H-pyrazol-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 469.1 11641-{1-[(1,5-Diphenyl-1H-pyrazol-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 499.1 12181-(1-{[2-(4-Chlorophenyl)-5-methyl-2H-1,2,3-triazol-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 472.1 8434-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]thiomorpholine 1,1-dioxide MS m/z (M + H⁺) 490.0 8154-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]morpholine MS m/z (M + H⁺) 442.0 12491-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}carbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺)491.1 13001-{1-[(2-Phenyl-2H-1,2,3-triazol-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 424.0 6464-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)piperidin-1-yl]benzonitrile MS m/z (M + H⁺) 465.1 7636-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3,4,9-tetrahydro-1H-carbazole MS m/z (M + H⁺) 450.1 7509-Methyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-9H-carbazole MS m/z (M + H⁺) 460.2 795N-Benzyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-thiazol-2-amine MS m/z (M + H⁺) 469.01225 1-(1-{[1-(3,4-Dichlorophenyl)-3,5-dimethyl-1H-pyrazol-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 519.0 636 1-(1-Hexadecanoylazetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 491.4 6871-Propyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 438.3 7761-{1-[(3,5-Di-tert-butylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 469.4 6371-(1-{[4-(4-Chlorophenyl)cyclohexyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 473.2 6721-{1-[(4-tert-Butylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 413.3 6691-{1-[(4-Pyrrolidin-1-ylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 426.3 8871-(1-{[4-(1,1-Dimethylpropyl)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 427.2 14341-[1-(4-Phenylbutanoyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 399.3 8881-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]azepane MS m/z (M + H⁺) 454.4 8891-{1-[(4-Cyclohexylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 439.2 8901-{1-[(1-Chloronaphtho[2,1-b]thiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 497.1 8911-(1-{[4-(2-Methylpropyl)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 413.3 8921-{1-[(4-Heptylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 455.3 8931-{1-[(4-Pentylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 427.2 6551-{1-[(4-Propylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 399.1 8941-{1-[(4-Butylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 413.3 8491-{1-[(5-tert-Butyl-2-methoxyphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 443.2 6391-{1-[(5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraenoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 539.4 6411-{1-[(9Z)-Octadec-9-enoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 517.3 6381-{1-[(9Z,12Z)-Octadeca-9,12-dienoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 515.4 1017Phenyl[4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]methanone MS m/z (M + H⁺) 461.1 10821-[1-({4-[4-(4-Fluorophenyl)-1,3-thiazol-2-yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 534.2 12451-[1-({4-[5-(4-Methylphenyl)-1H-1,2,3-triazol-1-yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 500.1 13261-(1-{[4-(4-Phenyl-1,3-thiazol-2-yl)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 516.2 13273-(4-Chlorophenyl)-2-[4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]-4,5,6,7-tetrahydro-2H-indazole MS m/z (M + H⁺) 587.3 11791-(1-{[4-(4,5-Diphenyl-1H-imidazol-2-yl)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 575.2 6931-(1-{[3-Chloro-4-(trifluoromethoxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 475.0 6674-(3-Chlorophenyl)-8-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline MS m/z (M + H⁺) 560.2 13281-[1-({4-[4-(2-Chlorophenyl)-1,3-thiazol-2-yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 550.0 13291-[1-({4-[4-(2,4-Dichlorophenyl)-1,3-thiazol-2-yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 584.1 6401-(1-Icosanoylazetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 547.3 1156 1-[1-({4-[5-(4-Methylphenyl)-1,3,4-oxadiazol-2-yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 515.2 13302-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]-3-[3-(trifluoromethyl)phenyl]-2,4,5,6-tetrahydrocyclopenta[c]pyrazole MS m/z (M + H⁺) 607.3 8267-Chloro-2-methyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M + H⁺) 456.1 7976-Chloro-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M + H⁺) 442.2 7877-Chloro-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M + H⁺) 442.2 8356-Chloro-2-methyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M + H⁺) 456.1 7436,7-Dichloro-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M + H⁺) 476.1 13311-[1-({4-[4-(3,4-Dichlorophenyl)-1,3-thiazol-2-yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 584.1 7271-{1-[(4-Bromo-3-methylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 447.1/449.1 7861-{1-[(4-Bromo-2-methylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 447.1/449.1 7661-{1-[(2,2-Dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 427.2 658N,N-Dipropyl-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)benzenesulfonamide MS m/z (M + H⁺) 520.2 816N-Ethyl-2-[4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]acetamide MS m/z (M + H⁺) 458.3 874Phenyl[5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-pyrrol-3-yl]methanone MS m/z (M + H⁺)450.1 1332 1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 584.1 13332-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 472.2 10831-(1-{[5-(4-Chlorophenyl)-1-(3,4-dichlorophenyl)-1H-pyrazol-3-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 601.0 7881-(1-{[2,5-Dimethyl-1-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 456.1 702 2-Chloro-5-fluoro-N-[4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]benzamide MSm/z (M + H⁺) 529.0 7701-[1-(3,4-Dihydro-2H-1,5-benzodioxepin-7-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 429.1 7832-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole MS m/z (M + H⁺) 428.1 6941-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[(2,2,2-trifluoroethoxy)methyl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z(M + H⁺) 469.2 836 N-{2-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]ethyl}acetamide MS m/z (M + H⁺) 458.3730 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4-(2,2,2-trifluoroethoxy)phenyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺)455.1 1334 1-[1-({4-[4-(4-Chlorophenyl)-1H-pyrazol-1-yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 533.1 12031-(4-Fluorophenyl)-3-methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-pyrazolo[3,4-b]pyridine MS m/z (M + H⁺) 506.2 11463-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[3-(trifluoromethyl)phenyl]-1H-thieno[2,3-c]pyrazole MS m/z (M + H⁺) 561.0 12721-{1-[(4-Methyl-2-pyridin-4-yl-1,3-thiazol-5-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 455.1 11192,3-Diphenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 548.2 8243-Methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-7,8-dihydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-4(6H)-one MS m/z (M + H⁺) 485.1 7103-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-9H-xanthen-9-one MS m/z (M + H⁺) 475.1 8235,7-Dichloro-2-methyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M +H⁺) 490.0 7821-(1-{[4-(2-Methoxyethoxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 431.3 6982-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-9H-fluoren-9-one MS m/z (M + H⁺) 459.1 11231-[1-({4-[4-(3,5-Difluorophenyl)-1H-pyrazol-1-yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 535.2 7915-Chloro-2,8-dimethyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M +H⁺) 470.1 845 7-Methoxy-2-methyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M +H⁺) 452.2 1412 1-[1-({4-[5-(4-Fluorophenyl)-1H-pyrazol-1-yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 518.1 946N-Methyl-N-phenyl-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)benzenesulfonamide MSm/z (M + H⁺) 526.0 10412-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]-N-[3-(trifluoromethyl)phenyl]acetamide MS m/z (M +H⁺) 574.0 10424-{[2,5-Dimethyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-pyrrol-1- yl]methyl}benzenesulfonamideMS m/z (M + H⁺) 544.0 9471-(1-{[4-(Piperidin-1-ylsulfonyl)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 504.1 10531-(4-Chlorobenzyl)-3-methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-thieno[2,3-c]pyrazole MS m/z (M + H⁺) 542.2 9521-{1-[(9,9-Dimethyl-9H-fluoren-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 473.0 14071-[1-({4-Methyl-2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): d 8.28 (s, 1H), 8.23 (d, 1H), 7.98 (d, 1H), 7.88(d, 1H), 7.82 (d, 1H), 7.72 (t, 1H), 4.35-4.81 (m, 6H), 3.92-4.13 (m,3H), 3.19-3.27 (m, 4H), 2.71 (s, 3H) MS m/z (M + H⁺) 522.2 13841-(1-{[2-(4-Chlorophenyl)-4-methyl-1,3-thiazol-5-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 488.1 13811-(1-{[2-(3-Chlorophenyl)-4-methyl-1,3-thiazol-5-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 488.1 11501-(1-{[2-(4-Fluorophenyl)-4-methyl-1,3-thiazol-5-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 472.0 13861-(1-{[2-(4-Fluorophenyl)-4-methyl-1,3-thiazol-5-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 472.0 13851-(1-{[2-Phenyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 492.1 13781-{1-[(2-Methyl-5-phenylfuran-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 437.1 13791-(1-{[5-Phenyl-2-(trifluoromethyl)furan-3-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 491.1 9651-[1-({2-[(4-Chlorophenoxy)methyl]-4-methyl-1,3-thiazol-5-yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 518.1 13921-(1-{[1-Phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 491.1 14031-(1-{[2-Phenyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 492.1 13961-{1-[(2-Methyl-5-phenylfuran-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 437.1 13971-(1-{[5-Phenyl-2-(trifluoromethyl)furan-3-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 491.1 9661-[1-({2-[(4-Chlorophenoxy)methyl]-4-methyl-1,3-thiazol-5-yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 518.1 14771-(1-{[1-Phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 491.1 1395 1-(1-{[2-(3,5-Dichlorophenyl)-1,3-thiazol-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 507.9/508.8 9231-(1-{[3-Bromo-5-(trifluoromethyl)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 503/505 9101-(1-{[3-Bromo-5-(trifluoromethyl)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 503/505 9151-{1-[(5-Bromo-2-fluorophenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 453/455 9121-{1-[(3-Bromo-5-fluorophenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 453/455 9251-{1-[(5-Bromo-2-fluorophenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 453/455 9261-{1-[(3-Bromo-5-fluorophenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 453/455 12021-(1-{[2-(2-Fluorophenyl)-4-methyl-1,3-thiazol-5-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 472.2 12871-(1-{[2-(2-Fluorophenyl)-4-methyl-1,3-thiazol-5-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 472.2 8311-(1-Methylethyl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)-1H- benzimidazole MSm/z (M + H⁺) 507.1 7401-(1-Methylethyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)-1H- benzimidazole MSm/z (M + H⁺) 507.1 14322-(2-Oxo-2-{3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}ethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide MS m/z(M + H⁺) 476.1 517 2-Phenyl-4-[1-(phenylcarbonyl)azetidin-3-yl]-1-{[5-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}piperazine MS m/z (M +H⁺) 550.03 14893-Methyl-2-phenyl-8-({2-phenyl-4-[1-(phenylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-4H-chromen-4-one MS m/z (M + H⁺) 584.341490 1-{1-[(5-Fluoro-3-methyl-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 422.06 5267-Methoxy-3-methyl-2-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 433.2 6101-[4-({4-[1-(Phenylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)phenyl]-1H-benzimidazole MS m/z (M + H⁺) 466.2 5231-Cyclohexyl-2-methyl-5-({4-[1-(phenylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 486.3 14911-{1-[(5-Chloro-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 424 6112-Phenyl-5-({4-[1-(phenylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 466.2 5241-[(5-Chloro-1-benzofuran-2-yl)carbonyl]-4-[1-(phenylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 432.9 5021-(Phenylcarbonyl)-4-(1-{[4-(trifluoromethyl)cyclohexyl]carbonyl}azetidin-3-yl)piperazine MS m/z(M + H⁺) 424 5031-(1-{[4-(4-Chlorophenyl)cyclohexyl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 466 6481-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(2E)-3-{4-[(trifluoromethyl)sulfanyl]phenyl}prop-2-enoyl]azetidin-3- yl}piperazineMS m/z (M + H⁺) 483.3 644 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[4-(trifluoromethyl)cyclohexyl]carbonyl}azetidin-3-yl)piperazine MS m/z(M + H⁺) 431.29 6431-(1-{[4-(4-Chlorophenyl)cyclohexyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 473.27 14814-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-phenyl-1-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 509.28 8042-Phenyl-4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]-1-{[5-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}piperazine MS m/z (M +H⁺) 557.14 9052-Phenyl-4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]-1-{[5-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}piperazine ¹H NMR(CDCl₃): δ 9.02 (d, 1H); 8.31 (s, 1H); 8.22 (s, 1H); 8.12 (m, 1H); 7.77(s, 1H); 7.69 (m, 1H); 7.50 (m, 5H); 7.35 (m, 1H); 5.91 (bm, 1H); 4.83(m, 1H); 4.64 (m, 1H); 4.48-4.46 (m, 2H); 4.14 (m, 1H); 3.86 (m, 1H);3.87 (m, 1H); 3.51 (m, 1H); 3.12 (t, 1H); 2.97 (m, 1H). MS m/z (M + H⁺)557.18 1436 3-Methyl-2-phenyl-8-({2-phenyl-4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-4H-chromen- 4-one MSm/z (M + H⁺) 591.26 8543-Methyl-2-phenyl-8-({2-phenyl-4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-4H-chromen- 4-one MSm/z (M + H⁺) 591.24 13071-(1-{[5-(4-Chlorophenyl)-1H-pyrrol-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 256 11221-{1-[(5-Phenylthiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.99 (d, 1H), 7.88 (d,1H); 7.71 9m, 2H); 7.52-7.32 (m, 4H); 4.75 (b, 4H); 4.0 (bm, 3H); 3.22(bm, 4H) MS m/z (M + H⁺) 439.16 14731-(1-{[5-(4-Chlorophenyl)-1,3-oxazol-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 458.13 8381-Methyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 410.12 7961,2-Dimethyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 424.21 14751-{1-[(3-Phenyl-1H-pyrazol-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 323.13 9931-Benzyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 486 8501-{1-[(6-Methoxy-3-methyl-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 441.1 721 1-{1-[(6-Methoxy-3-methyl-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 441.1 8621-{1-[(5-Fluoro-3-methyl-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 429.1 7511-{1-[(5-Fluoro-3-methyl-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 429.1 8407-Methoxy-3-methyl-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 440.1 760 7-Methoxy-3-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 440.1 1442 6-Fluoro-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 415 8467-Methoxy-3-methyl-2-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 439.7/440.3 8711-{1-[(7-Fluoro-3-methyl-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 428.8 8577-Methoxy-3-methyl-2-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 440.1 7555-Chloro-3-methyl-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 444.1 14435-Fluoro-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 415.2 7941-{1-[(7-Fluoro-3-methyl-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 428.8 6885-Chloro-3-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole ¹H NMR (CDCl₃): δ 7.88 (d, 1H);7.78 (d, 1H); 7.5 (m, 1H); 7.27 (m, 1H); 7.12 (m, 1H); 4.16 (bm, 1H);4.32 (bm, 2H); 3.16 (m, 3H); 2.36 (s, 3H) MS m/z (M + H⁺) 443.1 12931-[4-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]-1H-benzimidazole MS m/z (M + H⁺) 472.83 12231-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]-1H-benzimidazole MS m/z (M + H⁺) 473.1 13051-[4-({4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)phenyl]-1H-benzimidazole MS m/z (M + H⁺) 473.1 12981-[4-({4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)phenyl]-1H-benzimidazole MS m/z (M + H⁺) 473.1 7321-Cyclohexyl-2-methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 493.2 793 1-Cyclohexyl-2-methyl-5-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 493.2 8141-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}-4-(1-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 563.1 8002-Cyclohexyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 479.1 7352-Cyclohexyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 479.1 8272-Cyclohexyl-5-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 479.1 8532-Cyclohexyl-5-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 479.1 12992-Phenyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 473.1 11942-Phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 473.1 12712-Phenyl-5-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 473.1 14441-{1-[(5-Chloro-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 431 8181-{1-[(5-Chloro-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 431 7851-[(5-Chloro-1-benzofuran-2-yl)carbonyl]-4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 430.86 8091-[(5-Chloro-1-benzofuran-2-yl)carbonyl]-4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 430.93 10002-(2-Phenylethyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 501.1 10012-Benzyl-6-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 486.9 8555-Chloro-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole MS m/z (M + H⁺) 447.6 10022-(2-Phenylethyl)-6-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 501.1 7285-Chloro-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole MS m/z (M + H⁺) 448 7645-Chloro-2-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1,3-benzothiazole MS m/z (M + H⁺) 448 10032-Benzyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 487 10042-Benzyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 487 8215-Chloro-2-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1,3-benzothiazole MS m/z (M + H⁺) 448.1 7794-Chloro-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)quinoline MS m/z (M + H⁺)5.1 848 4-Chloro-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)quinoline MS m/z (M + H⁺)509.72 859 4-Chloro-6-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-2-(trifluoromethyl)quinoline MS m/z (M + H⁺)510 842 4-Chloro-6-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-2-(trifluoromethyl)quinoline MS m/z (M + H⁺)510 756 2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-indole MS m/z (M + H⁺) 463.81 8282-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-indole MS m/z (M + H⁺) 463.81 14452-({3-[4-(Isothiazol-5-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-indole MS m/z (M + H⁺) 463.81 7472-({4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-5-(trifluoromethyl)-1H-indole MS m/z (M + H⁺) 464.1 7722-({4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-5-(trifluoromethyl)-1H-indole MS m/z (M + H⁺) 464.1 7261-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}-4-[1-(1,3-thiazol-5-ylcarbonyl)azetidin-3- yl]piperazine MSm/z (M + H⁺) 494.97 7311-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}-4-[1-(1H-pyrrol-2-ylcarbonyl)azetidin-3- yl]piperazine MSm/z (M + H⁺) 477.02 7481-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}-4-[1-(1H-pyrrol-3-ylcarbonyl)azetidin-3- yl]piperazine MSm/z (M + H⁺) 477.02 8442-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)furo[2,3-b]pyridine MS m/z (M + H⁺)466.1 808 2-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)furo[2,3-b]pyridine MS m/z (M + H⁺)465.98 1446 2-({3-[4-(1H-Pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)furo[2,3-b]pyridine MS m/z (M + H⁺)448.2 860 2-({4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-6-(trifluoromethyl)furo[2,3-b]pyridine MS m/z (M + H⁺) 466678 1-[1-(Phenoxathiin-2-ylcarbonyl)azetidin-3-yl]-4-(1H-pyrrol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.38 (m, 2H); 7.19-6.84 (m, 5H);6.88 (m, 1H); 6.56 (m, 1H); 6.13 (m, 1H); 4.67-4.21 (m, 3H); 4.12-3.90(bd, 4H); 3.25 (bm, 3H) MS m/z (M + H⁺) 461.2 7992-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine MS m/z (M +H⁺) 465.2 8652-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine MS m/z (M +H⁺) 465.1 14472-({3-[4-(1H-Pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine MS m/z (M +H⁺) 447.1 1448 5-Bromo-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)furo[2,3-b]pyridine MS m/z (M + H⁺) 477.1 8645-Bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)furo[2,3-b]pyridine MS m/z (M + H⁺) 477.1 14495-Bromo-2-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)furo[2,3-b]pyridine MS m/z (M + H⁺) 477.1 6965-Chloro-1,3-dimethyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 458.2 758 5-Chloro-1,3-dimethyl-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 458.1 762 5-Chloro-1,3-dimethyl-2-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 485.1 839 5-Chloro-1,3-dimethyl-2-({4-[1-(1H-pyrrol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 440.2 774 3-Bromo-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine MS m/z (M + H⁺) 543.1 7335-Chloro-1,3-dimethyl-2-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 440.2 675 3-Bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine MS m/z (M + H⁺) 543.1 7393-Bromo-2-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine MS m/z (M + H⁺) 525.2 7463-Bromo-2-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine MS m/z (M + H⁺) 543 8632-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine MS m/z (M +H⁺) 465.1 8302-({4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine MS m/z (M +H⁺) 465.1 14502-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine MS m/z (M +H⁺) 465.1 7195-Fluoro-3-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 428.3 8526-Bromo-7-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine MS m/z (M + H⁺) 495.11451 6-Bromo-7-methyl-2-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine MS m/z (M + H⁺) 472.81452 8-Bromo-6-chloro-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine MS m/z (M + H⁺) 472.81453 2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine MS m/z (M + H⁺)465.1 682 5-Bromo-3-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 488.1 8686-Bromo-3-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine MS m/z (M + H⁺) 490.1873 6-Bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine MS m/z (M + H⁺) 475 8256-Bromo-3-methyl-2-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine MS m/z (M + H⁺) 471.1792 6-Bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 476.1 953(2R,6S)-2,6-Dimethyl-4-(1,3-thiazol-2-ylcarbonyl)-1-(1-{[6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 509.0

Example 6

A. Azetidin-3-one, 6a

The title compound 6a was prepared using the method described in Example1, substituting compound 4a for compound 1c in Procedure B. The crudecompound 6a was used in the next reaction without further purification.MS m/z (M+H⁺+CF₃CO₂H) 186.1.

B. 1-(4-Bromo-benzoyl)-azetidin-3-one, 6b

The title compound 6b was prepared using the method described in Example1, substituting compound 6a for compound 1g and substituting compound 2dfor compound 1h in Procedure E. The crude compound 6b was used in thenext reaction without further purification. MS m/z (M+H⁺) 419.2.

C. 4-[1-(4-Bromo-benzoyl)-azetidin-3-yl]-piperazine-1-carboxylic acidtert-butyl ester, 6c

The title compound 6c was prepared using the method described in Example4, substituting compound 6b for compound 4a and substituting compound 1afor compound 2a in Procedure A. The crude product 6c was purified byflash column chromatography. MS m/z (M+H⁺) 424.0/426.1.

D. (4-Bromo-phenyl)-(3-piperazin-1-yl-azetidin-1-A-methanone, 6d

The title compound 6d was prepared using the method described in Example1, substituting compound 6c for compound 1c in Procedure B. The crudeproduct 6d was used in the next reaction without further purification.MS m/z (M+H⁺) 324.08/326.08.

E.1-{1-[(4-Bromophenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 173

The title compound Cpd 173 was prepared using the method described inExample 1, substituting compound 6d for compound 1g and substitutingcompound 5c for compound 1h in Procedure E. The crude product Cpd 173was used in the next reaction without further purification. MS m/z(M+H⁺) 435.0/437.0.

F.1-{1-[(4′-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 174

To a suspension of compound 173 (0.05 g, 0.115 mmol), compound 6e(0.0193 g, 0.14 mmol), and Cs₂CO₃ (0.094 g, 0.288 mmol) in dioxane (3mL) and EtOH (1 mL) was added Pd(dppf)Cl₂ (0.0084 g, 0.0115 mmol). Thereaction mixture was stirred at 80° C. for 3 h. After cooling, the solidwas removed by filtration and washed with CH₃OH. The filtrate wasconcentrated. The crude compound 174 was purified by reverse phasechromatography. ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H),7.65-7.79 (m, 6H), 7.21 (t, 2H), 4.67 (m, 3H), 4.52 (m, 1H), 4.43 (m,1H), 4.31 (m, 1H), 3.98 (m, 2H), 3.89 (m, 1H), 3.11 (m, 4H); MS m/z(M+H⁺) 451.2 (calculated for C₂₄H₂₃FN₄O₂S, 450.54).

Following the procedure described above for Example 6 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 1751-{1-[(3′,4′-Dichlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.98 (d,1H), 7.88 (d, 1H), 7.85 (d, 1H), 7.77 (m, 4H), 7.62 (m, 2H), 4.54-4.81(m, 4H) 4.46 (m, 1H), 4.38 (m, 1H), 4.04 (m, 3H), 3.25 (m, 4H); LC/MSm/z (M + H⁺) 501.0/503.1 (calculated for C₂₄H₂₂Cl₂N₄O₂, 501.44) 1761-{1-[(3′-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H),7.87 (d, 1H), 7.74 (m, 4H), 7.45 (m, 2H), 7.35 (t, 1H), 7.22 (d, 1H),4.68 (m, 3H), 4.53 (m, 1H), 4.44 (m, 1H), 4.32 (m, 1H), 3.87-4.05 (m,3H), 3.15 (m, 4H); LC/MS m/z (M + H⁺) 447.1 (calculated for C₂₅H₂₆N₄O₂S,446.58) 177 1-{1-[(5′-Fluoro-2′-methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ7.97 (d, 1H), 7.87 (d, 1H), 7.76 (d, 2H), 7.46 (d, 2H), 7.30 (dd, 1H),7.02 (td, 1H), 6.94 (dd, 1H), 4.68 (m, 3H), 4.55 (m, 1H), 4.44 (m, 1H),4.33 (m, 1H), 4.01 (m, 2H), 3.92 (m, 1H), 3.14 (m, 4H); LC/MS m/z (M +H⁺) 465.1 (calculated for C₂₅H₂₅FN₄O₂S, 464.57) 1781-{1-[(3′-Chloro-4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ7.97 (d, 1H), 7.87 (d, 1H), 7.80 (dd, 1H), 7.76 (m, 4H), 7.64 (m, 1H),7.36 (t, 1H), 4.68 (m, 3H), 4.52 (m, 1H), 4.45 (m, 1H), 4.32 (m, 1H),3.89-4.06 (m, 3H), 3.16 (m, 4H); LC/MS m/z (M + H⁺) 485.1 (calculatedfor C₂₄H₂₂ClFN₄O₂S, 484.98) 1791-{1-[(2′,4′-Difluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d,1H), 7.87(d, 1H), 7.77 (d, 2H), 7.65 (d, 2H), 7.55 (m, 1H), 7.10 (m,2H), 4.65 (m, 3H), 4.50 (m, 1H), 4.42 (m, 1H), 4.30 (m, 1H), 3.97 (m,2H), 3.86 (m, 1H), 3.07 (m, 4H); LC/MS m/z (M + H⁺) 469.0 (calculatedfor C₂₄H₂₂F₂N₄O₂S, 468.53) 1801-{1-[(3′-Methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d,1H), 7.87 (d, 1H), 7.75 (m, 4H), 7.39 (t, 1H), 7.22 (d, 1H), 7.18 (t,1H), 6.97 (dd, 1H), 4.67 (m, 3H), 4.51 (m, 1H), 4.43 (m, 1H), 4.32 (m,1H), 3.96 (m, 3H), 3.86 (s, 3H), 3.15 (m, 4H); LC/MS m/z (M + H⁺) 463.2(calculated for C₂₅H₂₆N₄O₃S, 462.57) 1811-(1-{[4-(1,3-Benzodioxol-5-yl)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ7.98 (d, 1H), 7.87 (d, 1H), 7.70 (m, 4H), 7.16 (m, 2H), 6.92 (d, 1H),6.01 (s, 2H), 4.69 (m, 3H), 4.54 (m, 1H), 4.44 (m, 1H), 4.33(m, 1H),3.97 (m, 3H), 3.17 (m, 4H); LC/MS m/z (M + H⁺) 477.1 (calculated forC₂₅H₂₄N₄O₄S, 476.56) 1821-{1-[(4-Naphthalen-2-ylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ7.79-8.01 (m, 11H), 7.50- 7.56 (m, 2H), 4.60 (m, 1H), 4.49 (m, 1H), 4.37(m, 1H), 4.27 (m, 1H), 4.08 (m, 4H), 3.95 (m, 1H), 3.14 (m, 4H); LC/MSm/z (M + H⁺) 483.1 (calculated for C₂₈H₂₆N₄O₂S, 482.61) 1831-{1-[(3′-Nitrobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 8.53 (t, 1H),8.29 (m, 1H), 8.10 (m, 1H), 7.97 (d, 1H), 7.82-7.90 (m, 5H), 7.75 (t,1H), 4.69 (m, 3H), 4.55 (m, 1H), 4.46 (m, 1H), 4.34 (m, 1H), 3.88- 4.07(m, 3H), 3.15 (m, 4H); LC/MS m/z (M + H⁺) 478.2 (calculated forC₂₄H₂₃N₅O₄S, 477.55) 1845-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]quinoline ¹H NMR (300 MHz, CD₃OD): δ 9.14 (d, 1H),8.80 (d, 1H), 8.24 (d, 1H), 8.13 (dd, 1H), 7.97 (d, 1H), 7.89 (m, 5H),7.68 (m, 2H), 4.70 (m, 3H), 4.60 (m, 1H), 4.47 (m, 1H), 4.36 (m, 1H),4.00 (m, 2H), 3.91 (m, 1H), 3.12 (m, 4H); LC/MS m/z (M + H⁺) 484.2(calculated for C₂₇H₂₅N₅O₂S, 483.6) 1851-{1-[(2′,4′-Dimethoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 486.1 1861-(Phenylcarbonyl)-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.94 (m,2H), 7.80 (m, 4H), 7.70 (m, 2H), 7.45-7.53 (m, 5H), 4.66 (m, 1H), 4.52(m, 1H), 4.44 (m, 1H), 4.31 (m, 1H), 3.95 (m, 1H), 3.84 (m, 4H), 3.10(m, 4H); LC/MS m/z (M + H⁺) 494.1 (calculated for C₂₈H₂₆F₃N₃O₂, 493.53)187 1-{1-[(2′-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 444.1 1881-(1-{[3′-(1-Methylethoxy)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.73 (m,4H), 7.48 (m, 5H), 7.36 (t, 1H), 7.19 (d, 1H), 7.14 (t, 1H), 6.94 (dd,1H), 4.19- 4.82 (m, 5H), 3.83 (m, 5H), 2.98 (m, 4H), 1.34 (d, 6H); LC/MSm/z (M + H⁺) 484.2 (calculated for C₃₀H₃₃N₃O₃, 483.62) 1891-(Phenylcarbonyl)-4-(1-{4′-(trifluoromethoxy)biphenyl-4-yl]carbonyl}azetidin-3-yl)piperazine LC/MS m/z (M + H⁺) 510.1 1901-(1-{[4-(2-Fluoropyridin-4-yl)phenyl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 445.2 1911-{1-[(3′-Fluoro-4′-methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 474.1 192 Methyl4′-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-4-carboxylate LC/MS m/z (M + H⁺) 484.2 1931-(Phenylcarbonyl)-4-{1-[(3′,4′,5′-trifluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}piperazine LC/MS m/z (M + H⁺) 480.1 194N,N-Diethyl-4′-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-carboxamide LC/MS m/z (M + H⁺)525.3 195 1-{1-[(3′-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.76 (m, 4H),7.38-7.54 (m, 8H), 7.13 (m, 1H), 4.66 (m, 1H), 4.53 (m, 1H), 4.43 (m,1H), 4.31 (m, 1H), 3.95 (m, 1H), 3.83 (m, 4H), 3.11 (m, 4H); LC/MS m/z(M + H⁺) 444.1 (calculated for C₂₇H₂₆FN₃O₂, 443.53) 1961-(Phenylcarbonyl)-4-(1-{2′-(trifluoromethoxy)biphenyl-4-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.77(d,2H), 7.60 (d, 2H), 7.39-7.55 (m, 9H), 4.68 (m, 1H), 4.57 (m, 1H), 4.45(m, 1H), 4.33 (m, 1H), 3.97 (m, 1H), 3.83 (m, 4H), 3.13 (m, 4H); LC/MSm/z (M + H⁺) 510.1 (calculated for C₂₈H₂₆F₃N₃O₃, 509.53) 1971-{1-[(4′-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 440.2 1981-(1-{[2′-(1-Methylethoxy)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 484.2 199 Methyl4′-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-2-carboxylate LC/MS m/z (M + H⁺) 484.2 2001-{1-[(4′-Fluoro-2′-methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 474.3 2011-{1-[(2′,3′-Dimethoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 486.3 2021-{1-[(2′,5′-Difluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 462.1 2031-{1-[(2′-Fluoro-6′-methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 474.3 2041-{1-[(2′,3′-Difluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 462.1 205N,N-Dimethyl-N′-[4′-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]sulfamide ¹H NMR (300 MHz,CD₃OD): δ 7.73 (dd, 4H), 7.33-7.54 (m, 8H), 7.23 (dt, 1H), 4.18-4.72 (m,4H), 3.83 (m, 5H), 3.01 (m, 4H), 2.80 (s, 6H); LC/MS m/z (M + H⁺) 548.3(calculated for C₂₉H₃₃N₅O₄S, 547.68) 2064′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-carboxylic acid LC/MS m/z (M + H⁺) 477.1 207[4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]acetonitrile ¹H NMR (300 MHz, CD₃OD): δ 7.97(d, 1H), 7.87 (d, 1H), 7.78 (m, 4H), 7.65 (m, 2H), 7.51 (t, 1H), 7.42(d, 1H), 4.25- 4.76 (m, 6H), 4.00 (s, 2H), 3.86-4.03 (m, 3H), 3.13 (m,4H); LC/MS m/z (M + H⁺) 472.2 (calculated for C₂₆H₂₅N₅O₂S, 471.59) 2081-(1-{[3′-(Methylsulfonyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ8.22 (m, 1H), 7.95-8.07 (m, 3H), 7.71-7.90 (m, 6H), 4.31-4.81 (m, 6H),4.03 (m, 3H), 3.21- 3.36 (m, 4H), 3.19 (s, 3H); LC/MS m/z (M + H⁺) 511.2(calculated for C₂₅H₂₆N₄O₄S₂, 510.64) 2091-[4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-4-yl]ethanone ¹H NMR (300 MHz, CD₃OD): δ 8.11 (d,2H), 7.97 (d, 1H), 7.76-7.91 (m, 7H), 4.70 (m, 3H), 4.55 (m, 1H), 4.45(m, 1H), 4.34 (m, 1H), 3.98 (m, 3H), 3.16 (m, 4H), 2.65 (s, 3H); LC/MSm/z (M + H⁺) 475.2 (calculated for C₂₆H₂₆N₄O₃S, 474.59) 2104′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-carbaldehyde ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d,1H), 7.87 (d, 1H), 7.76 (m, 4H), 7.72 (m, 1H), 7.65 (m, 1H), 7.49 (m,2H), 4.69 (m, 3H), 4.53 (m, 1H), 4.44 (m, 1H), 4.32 (m, 1H), 3.96 (m,3H), 3.15 (m, 4H); LC/MS m/z (M + H⁺) 461.2 (calculated for C₂₅H₂₄N₄O₃S,460.56) 2114′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-4-ol ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H),7.86(d, 1H), 7.69 (m, 4H), 7.52 (d, 2H), 6.88 (d, 2H), 4.66 (m, 3H),4.51 (m, 1H), 4.42 (m, 1H), 4.29 (m, 1H), 3.98 (m, 2H), 3.86 (m, 1H),3.09 (m, 4H); LC/MS m/z (M + H⁺) 449.2 (calculated for C₂₄H₂₄N₄O₃S,448.55) 212 1-(1-{[4′-Chloro-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 8.03 (d, 1H), 7.97 (d, 1H), 7.92 (dd, 1H), 7.86(d, 1H), 7.80 (m, 4H), 7.73 (d, 1H), 4.62 (m, 3H), 4.45 (m, 2H), 4.28(m, 1H), 3.96 (m, 2H), 3.82 (m, 1H), 3.03 (m, 4H); LC/MS m/z (M + H⁺)535.0 (calculated for C₂₅H₂₂ClF₃N₄O₂S, 534.99) 213N,N-Dimethyl-4′-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-4-sulfonamide ¹H NMR (300 MHz,CD₃OD): δ 7.97 (d, 1H), 7.78-7.95 (m, 9H), 4.70 (m, 3H), 4.55 (m, 1H),4.45 (m, 1H), 4.34 (m, 1H), 3.97 (m, 3H), 3.17 (m, 4H), 2.72 (s, 6H);LC/MS m/z (M + H⁺) 540.2 (calculated for C₂₆H₂₉N₅O₄S₂, 539.68) 2141-{1-[(4′,5′-Difluoro-2′-methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.88 (d, 1H), 7.71 (d, 2H), 7.69(d, 2H), 7.26 (dd, 1H), 7.08 (dd, 1H), 4.70 (m, 3H), 4.56 (m, 1H), 4.46(m, 1H), 4.35 (m, 1H), 3.99 (m, 3H), 3.20 (m, 4H); LC/MS m/z (M + H⁺)499.2 (calculated for C₂₅H₂₄F₂N₄O₃S, 498.56) 2151-{1-[(4′-Nitrobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 8.36 (d, 2H),7.78-7.99 (m, 8H), 4.67 (m, 3H), 4.52 (m, 1H), 4.44 (m, 1H), 4.31 (m,1H), 3.98 (m, 2H), 3.99 (m, 1H), 3.12 (m, 4H); LC/MS m/z (M + H⁺) 478.2(calculated for C₂₄H₂₃N₅O₄S, 477.55) 2164-Methoxy-4′-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-carbaldehyde ¹H NMR (300 MHz,CD₃CN): δ 10.38 (s, 1H), 7.96 (d, 1H), 7.84-7.91 (m, 2H), 7.59-7.69 (m,5H), 7.19 (d, 1H), 4.33-4.64 (m, 4H), 4.23 (m, 2H), 3.91 (s, 3H), 3.89(m, 1H), 3.74 (m, 2H), 3.02 (m, 4H); LC/MS m/z (M + H⁺) 491.2(calculated for C₂₆H₂₆N₄O₄S, 490.59) 2174′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-carboxamide LC/MS m/z (M + H⁺) 476.1 2184′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-ol ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87(d, 1H), 7.72 (m, 4H), 7.28 (t, 1H), 7.11 (d, 1H), 7.06 (t, 1H), 6.82(dd, 1H), 4.64 (m, 3H), 4.49 (m, 1H), 4.40 (m, 1H), 4.28 (m, 1H), 3.96(m, 2H), 3.81 (m, 1H), 3.03 (m, 4H); LC/MS m/z (M + H⁺) 449.2(calculated for C₂₄H₂₄N₄O₃S, 448.55) 219N-[4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]methanesulfonamide ¹H NMR (300MHz, CD₃OD): δ 7.98 (d, 1H), 7.88 (d, 1H), 7.76 (m, 4H), 7.55 (t, 1H),7.45 (m, 2H), 7.28 (m, 1H), 4.73 (m, 3H), 4.60 (m, 1H), 4.47 (m, 1H),4.38 (m, 1H), 4.03 (m, 3H), 3.26 (m, 4H), 3.00 (s, 1H); LC/MS m/z (M +H⁺) 526.2 (calculated for C₂₅H₂₇N₅O₄S₂, 525.65) 220 tert-Butyl[4′-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]carbamate ¹H NMR (300 MHz,CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.80 (m, 1H), 7.75 (m, 4H), 7.37(m, 2H), 7.30 (m, 1H), 4.69 (m, 3H), 4.52 (m, 1H), 4.44 (m, 1H), 4.31(m, 1H), 3.85-4.07 (m, 3H), 3.13 (m, 4H), 1.53 (s, 9H); LC/MS m/z (M +H⁺) 548.3 (calculated for C₂₉H₃₃N₅O₄S, 547.68) 2211-(1-{[3′-(2-Methylpropoxy)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ7.97 (d, 1H), 7.87 (d, 1H), 7.75 (m, 4H), 7.37 (t, 1H), 7.21 (d, 1H),7.17 (t, 1H), 6.96 (dd, 1H), 4.67 (m, 3H), 4.52 (m, 1H), 4.43 (m, 1H),4.30 (m, 1H), 3.76-4.04 (m, 5H), 3.10 (m, 4H), 2.08 (m, 1H), 1.06 (d,6H); LC/MS m/z (M + H⁺) 505.2 (calculated for C₂₈H₃₂N₄O₃S, 504.66) 222N-(2-Cyanoethyl)-4′-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3- carboxamideLC/MS m/z (M + H⁺) 529.2 2233-[4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]prop-2-enenitrile ¹H NMR (300 MHz, CD₃OD): δ7.97 (d, 1H), 8.14 (s, 1H), 7.89 (m, 1H), 7.86 (d, 1H), 7.79 (m, 4H),7.76 (m, 1H), 7.50- 7.69 (m, 2H), 6.36 (d, 1H), 4.62 (m, 3H), 4.48 (m,1H), 4.40 (m, 1H), 4.27 (m, 1H), 4.95 (m, 2H), 3.77 (m, 1H), 3.00 (m,4H); LC/MS m/z (M + H⁺) 484.2 (calculated for C₂₇H₂₅N₅O₂S, 483.6) 224Methyl 3-[4′-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-4-yl]prop-2-enoate ¹H NMR (300 MHz,CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.79 (m, 4H), 7.74 (m, 5H), 6.60(d, 1H), 4.66 (m, 3H), 4.53 (m, 1H), 4.43 (m, 1H), 4.31 (m, 1H), 3.98(m, 2H), 3.88 (m, 1H), 3.80 (s, 3H), 3.11 (m, 4H); LC/MS m/z (M + H⁺)517.2 (calculated for C₂₈H₂₈N₄O₄S, 516.62) 2251-{1-[(4′-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H),8.22 (s, 1H), 7.74 (m, 4H), 7.69 (dd, 2H), 7.21 (t, 2H), 4.67 (m, 1H),4.56 (m, 1H), 4.45 (m, 1H), 4.34 (m, 1H), 3.94-4.22 (m, 5H), 3.18 (m,4H); LC/MS m/z (M + H⁺) 451.2 (calculated for C₂₄H₂₃FN₄O₂S, 450.54) 2261-{1-[(2′,4′-Difluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s,1H), 8.22 (s, 1H), 7.77 (d, 2H), 7.65 (d, 2H), 7.55 (m, 1H), 7.12 (m,1H), 7.08 (d, 1H), 4.69 (m, 1H), 4.57 (m, 1H), 4.45 (m, 1H), 4.36 (m,1H), 3.94-4.22 (m, 5H), 3.20 (m, 4H); LC/MS m/z (M + H⁺) 469.1(calculated for C₂₄H₂₂F₂N₄O₂S, 468.53) 2271-{1-[(3′-Chloro-4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ9.06 (s, 1H), 8.22 (s, 1H), 7.79 (dd, 1H), 7.76 (m, 4H), 7.63 (m, 1H),7.35 (t, 1H), 4.67 (m, 1H), 4.56 (m, 1H), 4.46 (m, 1H), 4.35 (m, 1H),3.95-4.23 (m, 5H), 3.21 (m, 4H); LC/MS m/z (M + H⁺) 485.1 (calculatedfor C₂₄H₂₂ClFN₄O₂S, 484.98) 2281-{1-[(3′,4′-Dichlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 8.96 (s,1H), 8.12 (s, 1H), 7.75 (d, 1H), 7.67 (m, 4H), 7.52 (m, 2H), 4.57 (m,1H), 4.50 (m, 1H), 4.37 (m, 1H), 4.27 (m, 1H), 3.88-4.15 (m, 5H), 3.13(m, 4H); LC/MS m/z (M + H⁺) 501.1 (calculated for C₂₄H₂₂Cl₂N₄O₂S,501.44) 229 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine ¹H NMR(300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.23 (s, 1H), 7.94 (m, 2H), 7.80 (m,4H), 7.70 (m, 2H), 4.67 (m, 2H), 4.45 (m, 2H), 4.01-4.29 (m, 5H), 3.30(m, 4H); LC/MS m/z (M + H⁺) 501.1 (calculated for C₂₅H₂₃F₃N₄O₂S, 500.55)230 4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-amine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H),7.87 (d, 1H), 7.79 (m, 4H), 7.75 (d, 1H), 7.63 (m, 2H), 7.38 (d, 1H),4.52- 4.80 (m, 4H), 4.45 (m, 1H), 4.38 (m, 1H), 3.89-4.10 (m, 3H), 3.17(m, 4H); LC/MS m/z (M + H⁺) 448.0 (calculated for C₂₄H₂₅N₅O₂S, 447.56)231 1-(1-{[3′-(Methylsulfonyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 504.0 2321-(1-{[4′-Chloro-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz,DMSO-d₆): δ 8.21 (s, 1H), 8.10 (d, 1H), 7.97 (d, 1H), 7.89 (d, 2H), 7.79(m, 3H), 7.48 (m, 4H), 4.62 (m, 2H), 4.40 (m, 1H), 4.30 (m, 1H), 4.10(m, 1H), 3.86 (m, 4H), 3.55 (m, 2H), 3.06 (m, 2H); LC/MS m/z (M + H⁺)528.0 (calculated for C₂₈H₂₅ClF₃N₃O₂, 527.98) 233N-[4′-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]acetamide LC/MS m/z (M + H⁺) 483.3 234N-[4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]acetamide ¹H NMR (300 MHz,DMSO-d₆): δ 8.10 (d, 1H), 8.06 (d, 1H), 8.00 (m, 1H), 7.75 (d, 2H), 7.70(d, 2H), 7.57 (dt, 1H), 7.34- 7.46 (m, 2H), 4.61 (m, 2H), 4.37 (m, 1H),4.29 (m, 1H), 4.05 (m, 1H), 3.35-3.82 (m, 6H), 3.09 (m, 2H), 2.07 (s,3H); LC/MS m/z (M + H⁺) 490.2 (calculated for C₂₆H₂₇N₅O₃S, 489.6) 235N-[4′-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]acetamide LC/MS m/z (MH+) 490.2236 1-(1-{[3′-(Methylsulfonyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 511.2 2371-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine ¹H NMR(300 MHz, DMSO-d₆): δ 8.01-8.14 (m, 4H), 7.88 (d, 2H), 7.67-7.83 (m,4H), 4.60 (m, 2H), 4.39 (m, 1H), 4.28 (m, 1H), 4.06 (m, 2H), 3.22-3.85(m, 5H), 3.10 (m, 2H); LC/MS m/z (M + H⁺) 501.1 (calculated forC₂₅H₂₃F₃N₄O₂S, 500.55) 2381-(1-{[3-Methyl-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz,CD₃OD): δ 7.85-7.94 (m, 2H), 7.40-7.73 (m, 10H), 4.42 (m, 1H), 4.26 (m,2H), 4.16 (m, 1H), 3.61-3.96 (m, 5H), 2.99 (m, 4H), 2.47 (s, 3H); LC/MSm/z (M + H⁺) 508.2 (calculated for C₂₉H₂₈F₃N₃O₂, 507.56) 2391-(1-{[3-Methyl-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 7.85-8.01 (m, 4H), 7.54-7.72 (m, 4H), 7.45 (d,1H), 4.69 (m, 2H), 4.44 (m, 1H), 4.29 (m, 2H), 4.20 (m, 1H), 3.99 (m,2H), 3.90 (m, 1H), 3.10 (m, 4H), 2.49 (s, 3H); LC/MS m/z (M + H⁺) 515.1(calculated for C₂₆H₂₅F₃N₄O₂S, 514.57) 2401-(1-{[3-Methyl-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 9.04 (s, 1H), 8.21 (s, 1H), 7.89 (m, 2H),7.51-7.72 (m, 4H), 7.45 (d, 1H), 3.87-4.54 (m, 9H) 3.14 (m, 4H), 2.48(s, 3H); LC/MS m/z (M + H⁺) 515.1 (calculated for C₂₆H₂₅F₃N₄O₂S, 514.57)241 1-(1-{[2-Methyl-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 7.98 (d, 1H), 7.88 (d, 1H), 7.54-7.77 (m, 6H),7.36 (d, 1H), 4.64-4.80 (m, 3H), 4.59 (m, H), 4.48 (m, 1H), 4.38 (m,1H), 3.92-4.12 (m, 3H), 3.27 (m, 4H), 2.30 (s, 3H); LC/MS m/z (M + H⁺)515.1 (calculated for C₂₆H₂₅F₃N₄O₂S, 514.57) 2421-(1-{[2-Methyl-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 9.07 (s, 1H), 8.22 (s, 1H), 7.49-7.78 (m, 6H),7.34 (d, 1H), 4.66 (m, 1H), 4.39-4.58 (m, 2H), 4.33 (m, 1H), 3.87-4.20(m, 5H), 3.14 (m, 4H), 2.31 (s, 3H); LC/MS m/z (M + H⁺) 515.1(calculated for C₂₆H₂₅F₃N₄O₂S, 514.57) 2431-(1-{[2-Methyl-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz,CD₃OD): δ 7.44-7.75 (m, 11H), 7.34 (d, 1H), 4.64 (m, 1H), 4.34-4.55 (m,2H), 4.29 (m, 1H), 3.66- 3.97(m, 5H), 3.03 (m, 4H), 2.30 (s, 3H); LC/MSm/z (M + H⁺) 508.2 (calculated for C₂₉H₂₈F₃N₃O₂, 507.56) 2441-(1-{[3-Fluoro-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 7.91-8.05 (m, 3H), 7.87 (d, 1H), 7.56-7.80 (m,5H), 4.60-4.77 (m, 2H), 4.38-4.51 (m, 2H), 4.24-4.38 (m, 2H), 3.84-4.09(m, 3H), 3.10 (m, 4H); LC/MS m/z (M + H⁺) 519.2 (calculated forC₂₅H₂₂F₄N₄O₂S, 518.54) 2451-(1-{[3-Fluoro-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.20 (s, 1H), 7.95 (m, 2H),7.55-7.80 (m, 5H), 4.38-4.51 (m, 2H), 4.25-4.38 (m, 2H), 3.86-4.19 (m,5H), 3.08 (m, 4H); LC/MS m/z (M + H⁺) 519.2 (calculated forC₂₅H₂₂F₄N₄O₂S, 518.54) 2461-(1-{[3-Fluoro-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz,CD₃OD): δ 7.90-8.01 (m, 2H), 7.56-7.80 (m, 5H), 7.42-7.56 (m, 5H),4.35-4.50 (m, 2H), 4.20-4.35 (m, 2H), 3.66-3.98 (m, 5H), 3.00 (m, 4H);LC/MS m/z (M + H⁺) 512.1 (calculated for C₂₈H₂₅F₄N₃O₂, 511.52) 2471-(1-{[2-Methoxy-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 7.79 (d, 1H), 7.88 (d, 1H), 7.71-7.82 (m, 2H),7.56-7.69 (m, 2H), 7.45 (d, 1H), 7.39 (d, 1H), 7.34 (dd, 1H), 4.61-4.78(m, 3H), 4.57 (m, 1H), 4.46 (m, 1H), 4.34 (m, 1H), 3.87-4.06 (m, 3H),3.89 (s, 3H), 3.17 (m, 4 H); LC/MS m/z (M + H⁺) 531.2 (calculated forC₂₆H₂₅F₃N₄O₃S, 530.57) 2481-(1-{[2-Methoxy-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.22 (s, 1H), 7.71-7.81 (m, 2H),7.55-7.69 (m, 2H), 7.45 (d, 1H), 7.38 (s, 1H), 7.33 (dd, 3H), 4.70 (m,1H), 4.58 (m, 1H), 4.47 (m, 1H), 4.36 (m, 1H), 3.94-4.25 (m, 5H), 3.89(s, 3H), 3.21 (m, 4H); LC/MS m/z (M + H⁺) 531.2 (calculated forC₂₆H₂₅F₃N₄O₃S, 530.57) 2491-(1-{[2-Methoxy-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz,CD₃OD): δ 7.72-7.84 (m, 2H), 7.56-7.71 (m, 2H), 7.27-7.56 (m, 8H), 4.66(m, 1H), 4.37-4.59 (m, 2H), 4.32 (m, 1H), 3.66-4.03 (m, 8H), 3.08 (m,4H); LC/MS m/z (M + H⁺) 524.3 (calculated for C₂₉H₂₈F₃N₃O₃, 523.56) 2501-(1-{[3-Chloro-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 7.90-8.03 (m, 3H), 7.82-7.90 (m, 2H), 7.62-7.79(m, 3H), 7.57 (d, 1H), 4.62-4.78 (m, 2H), 4.41-4.54 (m, 1H), 4.20-4.40(m, 3H), 3.90-4.10 (m, 3H), 3.02- 3.24 (m, 4H); LC/MS m/z (M + H⁺) 535.0(calculated for C₂₅H₂₂ClF₃N₄O₂S, 534.99) 2511-(1-{[3-Chloro-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 9.05 (s, 1H), 8.20 (s, 1H), 7.90-8.02 (m, 2H),7.85 (s, 1H), 7.63-7.81 (m, 3H), 7.56 (d, 1H), 4.40-4.54 (m, 1H),4.17-4.38 (m, 3H), 3.85-4.17 (m, 5H), 2.98-3.15 (m, 4H); LC/MS m/z (M +H⁺) 535.0 (calculated for C₂₅H₂₂ClF₃N₄O₂S, 534.99) 2521-(1-{[3-Chloro-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz,CD₃OD): δ 7.87-7.97 (m, 2H), 7.84 (d, 1H), 7.64-7.79 (m, 3H), 7.55 (d,1H), 7.41-7.52 (m, 5H), 4.41 (dd, 1H), 4.21-4.34 (m, 2H), 4.17 (dd, 1H),3.65-3.99 (m, 5H), 2.94 (m, 4H); LC/MS m/z (M + H⁺) 528.2 (calculatedfor C₂₈H₂₅ClF₃N₃O₂, 527.98) 2531-{1-[(3′-Chloro-4′-fluoro-3-methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 9.05 (s, 1H), 8.19 (d, 1H), 7.75 (dd, 1H),7.55-7.66 (m, 2H), 7.51 (dd, 1H), 7.27-7.45 (m, 2H), 4.42 (dd, 1H),4.21-4.34 (m, 2H), 3.95-4.21 (m, 5H), 3.88 (m, 1H), 2.94-3.15 (m, 4H),2.46 (s, 3H); LC/MS m/z (M + H⁺) 499.0 (calculated for C₂₅H₂₄ClFN₄O₂S,499.01) 254 1-(1-{[4′-Chloro-3-methyl-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 9.05 (s, 1H), 8.19 (d, 1H), 7.98 (d, 1H), 7.88(dd, 1H), 7.71 (d, 1H), 7.63 (m, 1H), 7.57 (dd, 1 H), 7.45 (d, 1H), 4.44(dd, 1H), 4.23-4.35 (m, 2H), 3.85- 4.23 (m, 6H), 2.96-3.19 (m, 4H), 2.48(s, 3H); LC/MS m/z (M + H⁺) 549.2 (calculated for C₂₆H₂₄ClF₃N₄O₂S,549.02) 255 1-{1-[(3′-Chloro-4′-fluoro-3-methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz,CD₃OD): δ 7.75 (dd, 1H), 7.28-7.65 (m, 10H), 4.38 (dd, 1H), 4.16-4.29(m, 2H), 4.10(m, 1H), 3.60-3.95 (m, 5H), 2.91 (m, 4H), 2.45 (s, 3 H);LC/MS m/z (M + H⁺) 492.1 (calculated for C₂₈H₂₇ClFN₃O₂, 492.00) 2561-(1-{[4′-Chloro-3-methyl-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz,CD₃OD): δ 7.97 (m, 1H), 7.87 (dd, 1H), 7.71 (d, 1H), 7.62 (m, 1H), 7.56(m, 1H), 7.38-7.52 (m, 6H), 4.39 (dd, 1H), 4.16-4.28 (m, 2H), 4.11 (m,1H), 3.63-3.93 (m, 5H), 2.91 (m, 4H), 2.47 (s, 3H); LC/MS m/z (M + H⁺)542.1 (calculated for C₂₉H₂₇ClF₃N₃O₂, 542.01) 2571-{1-[(3′-Chloro-4′-fluoro-2-methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.20 (s, 1H), 7.49-7.67 (m, 2H),7.44 (dd, 1H), 7.20-7.37 (m, 3H), 4.63 (m, 1H), 4.37-4.56 (m, 2H), 4.31(m, 1H), 3.84-4.19 (m, 5H), 3.12 (m, 4H), 2.30(s, 3H); LC/MS m/z (M +H⁺) 499.0 (calculated for C₂₅H₂₄ClFN₄O₂S, 499.01) 2581-(1-{[4′-Chloro-2-methyl-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.20 (s, 1H), 7.66-7.76 (m, 2H),7.51-7.65 (m, 3H), 7.36 (d, 1H), 4.63 (m, 1H), 4.37-4.56 (m, 2H), 4.29(m, 1H), 3.84-4.21 (m, 5H), 3.09 (m, 4H), 2.30(s, 3H); LC/MS m/z (M +H⁺) 549.2 (calculated for C₂₆H₂₄ClF₃N₄O₂S, 549.02) 2591-{1-[(3′-Chloro-4′-fluoro-2-methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz,CD₃OD): δ 7.59 (m, 1H), 7.40-7.57 (m, 7H), 7.23-7.39 (m, 3H), 4.65 (m,1H), 4.37-4.58 (m, 2H), 4.32 (m, 1H), 3.67-4.05 (m, 5H), 3.11 (m, 4H),2.30 (s, 3H); LC/MS m/z (M + H⁺) 492.1 (calculated for C₂₈H₂₇ClFN₃O₂,492.00) 260 1-(1-{[4′-Chloro-2-methyl-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz,CD₃OD): δ 7.70-7.80 (m, 3H), 7.42-7.68 (m, 7H), 7.35 (d, 1H), 4.63 (m,1H), 4.34-4.55 (m, 2H), 4.28 (m, 1H), 3.67-3.98 (m, 5H), 3.02 (m, 4H),2.30 (s, 3H); LC/MS m/z (M + H⁺) 542.1 (calculated for C₂₉H₂₇ClF₃N₃O₂,542.01) 261 1-{1-[(3′-Chloro-4′-fluoro-2-methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.20 (s, 1H), 7.61 (d, 1H),7.20-7.50 (m, 5H), 4.67 (m, 1H), 4.55 (m, 1H), 4.43 (m, 1H), 4.31 (m,1H), 3.90-4.25 (m, 5H), 3.90 (s, 3H), 3.11 (m, 4H); LC/MS m/z (M + H⁺)515.1 (calculated for C₂₅H₂₄ClFN₄O₃S, 515.01) 2621-(1-{[4′-Chloro-2-methoxy-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.74(dd, 1H), 7.66 (d, 1H), 7.45 (d, 1H), 7.38 (m, 1H), 7.33 (dd, 1H), 4.65(m, 1H), 4.33-4.56 (m, 2H), 4.26 (m, 1H), 3.89-4.12 (m, 5H), 3.89 (s,3H), 2.97 (m, 4H); LC/MS m/z (M + H⁺) 565.0 (calculated forC₂₆H₂₄ClF₃N₄O₃S, 565.02) 2631-{1-[(3′-Chloro-4′-fluoro-2-methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz,CD₃OD): δ 7.61 (dd, 1H), 7.38-7.57 (m, 7H), 7.35 (d, 1H), 7.23-7.33 (m,2H), 4.65 (m, 1H) 4.36-4.57 (m, 2H), 4.30 (m, 1H), 3.88 (s, 3H),3.67-3.97 (m, 5H), 3.05 (m, 4H); LC/MS m/z (M + H⁺) 508.0 (calculatedfor C₂₈H₂₇ClFN₃O₃, 508.00) 2641-(1-{[4′-Chloro-2-methoxy-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz,CD₃OD): δ 7.88 (d, 1H), 7.74 (dd, 1H), 7.66 (d, 1H), 7.42-7.57 (m, 6H),7.38 (m, 1H), 7.32 (dd, 1H), 4.58-4.69 (m, 1H), 4.36-4.58 (m, 2H),4.20-4.33 (m, 1H), 3.89 (s, 3H), 3.60-4.04 (m, 5H), 3.03 (m, 4 H); LC/MSm/z (M + H⁺) 558.2 (calculated for C₂₉H₂₇ClF₃N₃O₃, 558.01) 2651-{1-[(3,3′-Dichloro-4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ9.05 (s, 1H), 8.18 (s, 1H), 7.77-7.83 (m, 2H), 7.68 (dd, 1H), 7.58-7.67(m, 1H), 7.53 (d, 1H), 7.36 (t, 1H), 4.42 (dd, 1H), 4.22-4.35 (m, 2H),4.18 (dd, 1H), 3.80-4.13 (m, 5H), 2.90-3.11 (m, 4H); LC/MS m/z (M + H⁺)519.0 (calculated for C₂₄H₂₁Cl₂FN₄O₂S, 519.43) 2661-(1-{[3,4′-Dichloro-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹HNMR (300 MHz, CD₃OD): δ 9.05 (s, 1H), 8.18 (s, 1H), 8.01 (m, 1H),7.81-7.98 (m, 2H), 7.74 (d, 2H), 7.56 (d, 1H), 4.36- 4.49 (dd, 1H),4.22-4.35 (m, 2H), 4.19 (dd, 1H), 3.80-4.13 (m, 5H), 2.90-3.11 (m, 4H);LC/MS m/z (M + H⁺) 569.0 (calculated for C₂₅H₂₁Cl₂F₃N₄O₂S, 569.44) 2671-{1-[(3,3′-Dichloro-4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.77-7.84(m, 2H), 7.58-7.71 (m, 2H), 7.42-7.57 (m, 6H), 7.36 (t, 1H), 4.42 (dd,1H) 4.13- 4.34 (m, 3H), 3.62-4.01 (m, 5H), 2.98 (m, 4H); LC/MS m/z (M +H⁺) 512.1 (calculated for C₂₇H₂₄Cl₂FN₃O₂, 512.42) 2681-(1-{[3,4′-Dichloro-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz,CD₃OD): δ 8.01 (d, 1H), 7.90 (dd, 1H), 7.85 (d, 1H), 7.74 (d, 2H), 7.56(d, 1H), 7.41-7.53 (m, 5H), 4.43 (dd, 1H), 4.14-4.35 (m, 3H), 3.63-4.04(m, 5H), 2.99 (m, 4H); LC/MS m/z (M + H⁺) 562.0 (calculated forC₂₈H₂₄Cl₂F₃N₃O₂, 562.42) 4881-{1-[(3-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H),8.22 (s, 1H), 7.30-7.71 (m, 8H), 3.92-4.57 (m, 9H) 3.11-3.29 (m, 4H),2.46(s, 3H); LC/MS m/z (M + H⁺) 447.1 (calculated for C₂₅H₂₆N₄O₂S,446.58) 1070 1-(1-{[2-Fluoro-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 518.9 1102 1-(1-{[2-Chloro-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 434.9

Example 7

A. 2,2,2-Trifluoro-1-[4-(thiazole-2-carbonyl)-piperazin-1-yl]-ethanone,7a

To a solution of compound 1d (5 g, 0.027 mol) in DMF (50 mL) and DIPEA(19.5 mL, 0.11 mol) was added compound 5c (3.3 g, 0.0255 mol) and HATU(12.6 g, 0.033 mol). The reaction was stirred for 4 h then poured intowater and extracted with EtOAc. The organic portions were washed withwater and brine, and dried over MgSO₄. The solvent was evaporated invacuo. The residue was passed through a silica gel column (30-10%:EtOAc-heptane) to give compound 7a (3.8 g). MS m/z (M+H⁺) 294.1.

B. Piperazin-1-yl-thiazol-2-yl-methanone, 7b

A solution of compound 7a (3.8 g, 0.013 mol) and K₂CO₃ (3.5 g, 0.026mol) in MeOH (40 mL) and water (10 mL), was stirred for 4 h. The solidwas collected by filtration and the solvent evaporated in vacuo to givecompound 7b (6.12 g). MS m/z (M+H⁺) 198.1.

C. 3-[4-(Thiazole-2-carbonyl)-piperazin-1-yl]-azetidine-1-carboxylicacid tert-butyl ester, 7c

A solution of compound 7b (6.1 g, 0.031 mol) and (5.1 g, 0.03 mol)compound 4a in MeOH (30 mL) was stiffed for 15 min Decaborane (1 g,0.008 mol) was added and the reaction was stirred for 18 h. The solventwas evaporated in vacuo. The residue was used without furtherpurification for the next step. MS m/z (M+H⁺) 353.1.

D. (4-Azetidin-3-yl-piperazin-1-yl)-thiazol-2-ylmethanone, 5e

To a solution of compound 7c in CH₂Cl₂ (100 mL) was added TFA (30 mL).The reaction was stirred for 3.5 h and the solvent was evaporated invacuo. The residue was purified by reverse phase preparative HPLC togive compound 5e (5.15 g). MS m/z (M+H⁺) 253.1.

E.1-{1-[3-(4-Chlorophenyl)propanoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 269

To a solution of compound 5e (150 mg, 0.52 mmol) in DMF (5 mL) and DIPEA(0.40 mL, 2.2 mmol) was added compound 7d (125 mg, 0.067 mmol), and HATU(0.25 g, 0.067 mmol). The reaction was stirred for 4 h, then poured intowater and extracted with EtOAc. The combined extracts were concentratedin vacuo. The resultant residue was purified by reverse phase HPLC togive compound 269 (20.2 mg). LC/MS m/z (M+H⁺) 419.15 (calculated forC₂₀H₂₃ClN₄O₂S, 418.95).

Following the procedure described above for Example 7 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared.

Cpd Cpd Name and Data 2701-{1-[3-(4-Bromophenyl)propanoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + 2H⁺) 465.05 (calculatedfor C₂₀H₂₃BrN₄O₂S, 463.40) 271 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{3-[4-(trifluoromethyl)phenyl]propanoyl}azetidin-3-yl)piperazine. LC/MS m/z(M + H⁺) 453.15 (calculated for C₂₁H₂₃F₃N₄O₂S, 452.50) 2721-{1-[3-(3-Chlorophenyl)propanoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 419.17 (calculatedfor C₂₀H₂₃ClN₄O₂S, 418.95) 2731-{1-[3-(2-Chlorophenyl)propanoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine. ¹H NMR (300 MHz, MeOD): δ 8.0 (d, 1H),7.9 (d, 2H), 4.7 (bm, 2H), 4.4 (m, 2H), 4.3-4.1 (m, 2H), 4.0 (bm, 2H),3.25 (m, 5H), 3.0 (m, 2H), 2.5 (m, 2H) LC/MS m/z (M + H⁺) 419.16(calculated for C₂₀H₂₃ClN₄O₂S, 418.95) 2741-{1-[3-(2,6-Dichlorophenyl)propanoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine. ¹H NMR (300 MHz, MeOD): δ 8 (d, 1H),7.9 (d, 1H), 7.4 (ar, 2H), 7.2 (m, 1H), 4.75 (m, 2H), 4.5-4.1 (m, 5H),4.0 (m, 3H), 3.2 (m, 5H), 2.4 (m, 3H) LC/MS m/z (M + 2H⁺) 455.10(calculated for C₂₀H₂₂Cl₂N₄O₂S, 453.39) 2751-{1-[3-(3,4-Difluorophenyl)propanoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 421.19 (calculatedfor C₂₀H₂₂F₂N₄O₂S, 420.48) 2761-{1-[3-(4-Methylphenyl)propanoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 399.23 (calculatedfor C₂₁H₂₆N₄O₂S, 398.53) 2771-{1-[3-(4-Methoxyphenyl)propanoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine3 LC/MS m/z (M + H⁺) 415.23 (calculatedfor C₂₁H₂₆N₄O₃S, 414.53) 2781-(1-{3-[3,5-Bis(trifluoromethyl)phenyl]propanoyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 521.14(calculated for C₂₂H₂₂F₆N₄O₂S, 520.50) 2791-[1-(3-Naphthalen-1-ylpropanoyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 435.22 (calculated forC₂₄H₂₆N₄O₂S, 434.56) 2801-{1-[3-(4-Phenoxyphenyl)propanoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 477.20 (calculatedfor C₂₆H₂₈N₄O₃S, 476.60) 2811-{1-[3-(3,4-Dichlorophenyl)propanoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine. ¹H NMR (300 MHz, MeOD) d 8.0 (ar, 1H),7.9 (ar, 1H), 7.4 (m, 2H), 7.2 (m, 1H), 4.4 (dd, 1H), 4.3-4.2 (m, 2H),4.1 (m, 1H), 3.9 (m, 1H), 3.3 (m, 3H), 3.2 (m, 4H), 3.0 (bs, 1H), 2.9(m, 2H), 2.5 (m, 2H) LC/MS m/z (M + 2H⁺) 455.10 (calculated forC₂₀H₂₂Cl₂N₄O₂S, 453.39) 2821-{1-[3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)propanoyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine. ¹HNMR (300 MHz, MeOD): δ 7.9 (ar, 1H), 7.7 (ar, 1H), 7.13 (ar, 1H), 7.0(ar, 1H), 6.9 (ar, 1H), 4.2-4.1 (m, 2H), 4.1-4.0 (m, 1H), 3.9, (bs, 1H),3.8 (m, 1H), 3.2 (m, 2H), 3.11 (m, 4H), 2.7 (t, 2H), 2.3 (t, 2H), 1.5(s, 4H), 1.1 (dd, 12H). LC/MS m/z (M + H⁺) 495.24 (calculated forC₂₈H₃₈N₄O₂S, 494.70) 283 1-(1,3-Thiazol-2-ylcarbonyl)-4-{l-[(2E)-3-{4-[(trifluoromethyl)sulfanyl]phenyl}prop-2-enoyl]azetidin-3- yl}piperazineLC/MS m/z (M + H⁺) 483.18 (calculated for C₂₁H₂₁F₃N₄O₂S₂, 482.55) 2841-{1-[(3-Chlorophenoxy)acetyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 421.12 (calculated forC₁₉H₂₁ClN₄O₃S, 420.92) 2851-{1-[(2-Chlorophenoxy)acetyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 421.12 (calculated forC₁₉H₂₁ClN₄O₃S, 420.92) 2861-{1-[3-(2-Bromophenyl)propanoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + 2H⁺) 465.07 (calculatedfor C₂₀H₂₃BrN₄O₂S, 463.40) 287 1-(1-{3-[4-(3,4-Dimethyl-1H-pyrazol-1-yl)phenyl]propanoyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 479.29 (calculated forC₂₅H₃₀N₆O₂S, 478.62) 2881-{1-[(2,4-Dichlorophenoxy)acetyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + 2H⁺) 457.13 (calculatedfor C₁₉H₂₀Cl₂N₄O₃S, 455.37) 289 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4-(trifluoromethoxy)phenoxy]acetyl}azetidin-3-yl)piperazine. LC/MS m/z(M + H⁺) 471.16 (calculated for C₂₀H₂₁F₃N₄O₄S, 470.47) 290N-Cyclopropyl-4-(3-oxo-3-{3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}propyl)benzenesulfonamide. ¹HNMR (300 MHz, MeOD) d 8.0 (d, 1H); 7.9 (d, 1H); 7.4 (m, 4H); 4.7 (bs,2H), 4.4-4.1 (m, 3H), 4.1-3.9 (m, 3H), 3.8 (m, 1H), 3.1 (m, 3H), 3.0 (t,2H), 2.5 (t, 2H), 2.1 m, 1H), 0.5 (m, 4H) LC/MS m/z (M + H⁺) 504.20(calculated for C₂₃H₂₉N₅O₄S₂, 503.65) 291N-(Cyclohexylmethyl)-N-methyl-4-(3-oxo-3-{3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}propyl)aniline. ¹H NMR (300MHz, MeOD): δ 8.0 (d, 1H), 7.9 (d, 1H), 7.5 (m, 4H), 4.4 (bm, 2H),4.25-4.0 (m, 4H), 3.8 (m, 1H), 3.4 (d, 2H), 3.2 (s, m, 3H), 3.1 (bs,3H), 3.0 (t, 2H), 2.5 (t, 2H), 1.7 (m, 5H), 1.1 (m, 5H) LC/MS m/z (M +H⁺) 510.32 (calculated for C₂₈H₃₉N₅O₂S, 509.72) 2921-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({[4-(trifluoromethyl)phenyl]sulfanyl}acetyl)azetidin-3- yl]piperazine LC/MSm/z (M + H⁺) 471.18 (calculated for C₂₀H₂₁F₃N₄O₂S₂, 470.54) 293l-[1-(1-Benzothiophen-2-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 413.20 (calculatedfor C₂₀H₂₀N₄O₂S₂, 412.54) 2941-{1-[3-(4-Ethoxyphenyl)propanoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 429.27 (calculatedfor C₂₂H₂₈N₄O₃S, 428.56) 2951-{1-[(2E)-3-(2-Chlorophenyl)prop-2-enoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 417.0(calculated for C₂₀H₂₁ClN₄O₂S, 416.93) 2961-{1-[(2E)-3-(2-Bromophenyl)prop-2-enoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 462.9(calculated for C₂₀H₂₁BrN₄O₂S, 461.38) 2973-Naphthalen-2-yl-1-{3-[4-(thiazole-2-carbonyl)-piperazin-1-yl]-azetidin-1-yl}-propenone LC/MS m/z (M + H⁺) 433.29 (calculated forC₂₄H₂₄N₄O₂S, 432.55)

Example 8

A. 4-(1-Benzhydryl-azetidin-3-yl)-piperazine-1-carboxylic acid benzylester, 8b

To a solution of compound 8a (1.4 g, 6.3 mmol) and compound 1e (2 g, 6.3mmol) in CH₃CN (30 mL) was added DIPEA (1.5 mL, 8.1 mmol) at roomtemperature. The mixture was refluxed for 18 h. The solvent was removedunder reduced pressure and the residue was partitioned between CHCl₃ andwater. The organic layer was dried over K₂CO₃, filtered, andconcentrated to give crude compound 8b (2.65 g). MS m/z (M+H⁺) 442.

B. 4-Azetidin-3-yl-piperazine-1-carboxylic acid benzyl ester, 8c

To a solution of compound 8b (3.4 g, 7.7 mmol) in CH₂Cl₂ was added1-chloroethyl chloroformate (2.5 mL, 23.1 mmol) at 0° C. under a N₂atmosphere. The ice bath was removed and the reaction stirred for 2 h.The organic phase was concentrated under reduced pressure, and MeOH wasadded to the resultant residue. The reaction was refluxed for 2 h atwhich time the solvent was removed under reduced pressure. The residuewas partitioned between chloroform and aqueous HCl (1N). The aqueouslayer was separated, made basic with aqueous NaOH (3N), and extractedwith chloroform. The organic layer was then dried (K₂CO₃), filtered andconcentrated to afford compound 8c (2.65 g). MS m/z (M+H⁺) 276.

C. 4-[1-(Biphenyl-4-carbonyl)-azetidin-3-yl]-piperazine-1-carboxylicacid benzyl ester, 8e

To a solution of compound 8c (2.6 g, 9.4 mmol), compound 8d (1.87 g, 9.4mmol), and DIPEA (2.43 g, 18.9 mmol) in acetonitrile was added HBTU (4.6g, 12.3 mmol). The reaction was stirred for 18 h at which time thesolvent was removed under reduced pressure and the crude productpurified by reverse phase HPLC. Lyophilization provided compound 8e(1.74 g). MS m/z (M+H⁺) 456.2.

D. Biphenyl-4-yl-(3-piperazin-1-yl-azetidin-1-yl)-methanone, 8f

A mixture of compound 8e (1.7 g, 2.9 mmol), and 10% Palladium on carbon(300 mg) was hydrogenated (50 psi hydrogen gas) using a Parr apparatusfor 18 h. The catalyst was removed by filtration, and the solventconcentrated under reduced pressure to afford crude compound 8f (1.5 g).MS m/z (M+H⁺) 322.

E.1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(4-fluorophenyl)-carbonyl]piperazine,Cpd 299

To a solution of compound 8f (100 mg, 0.3 mmol), compound 8g (44 mg,0.31 mmol), and DIPEA (80 mg, 0.6 mmol) in dimethylformamide was addedHBTU (141 mg, 0.37 mmol). After stirring for 18 h, the reaction waspurified by preparative reverse phase HPLC to yield compound 299. ¹H NMR(400 MHz, MeOD): δ 7.93-8.03 (m, 1H), 7.61-7.71 (m, 4H), 7.54-7.61 (m,2H), 7.43-7.50 (m, 2H), 7.35-7.43 (m, 2H), 7.27-7.35 (m, 1H), 7.07-7.20(m, 2H), 4.55-4.67 (m, 1H), 4.43-4.53 (m, 1H), 4.32-4.43 (m, 1H),4.19-4.32 (m, 1H), 3.89-4.00 (m, 1H), 3.66-3.89 (m, 4H), 3.08 (br. s.,4H); MS m/z (M+H⁺) 444.2 (calculated for C₂₇H₂₆FN₃O₂, 443.53).

Following the procedure described above for Example 8 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 3001-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(2-fluorophenyl)carbonyl]piperazine MS m/z (M + H⁺) 444.2 (calculated forC₂₇H₂₆FN₃O₂, 443.53) 3011-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(thiophen-3-ylcarbonyl)piperazine MS m/z (M + H⁺) 432.1 (calculated for C₂₅H₂₅N₃O₂S,431.56) 302 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1H-pyrrol-2-ylcarbonyl)piperazine MS m/z (M + 2H⁺) 416.2 (calculated for C₂₅H₂₆N₄O₂,414.51) 303 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(cyclopropylcarbonyl)piperazine MS m/z (M + H⁺) 390.23 (calculated forC₂₄H₂₇N₄O₂, 389.5) 304 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(3-fluorophenyl)carbonyl]piperazine MS m/z (M + H⁺) 444.2 (calculated forC₂₇H₂₆FN₃O₂, 443.53) 3051-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-oxazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 417.2 (calculated for C₂₄H₂₄N₄O₃,416.48) 306 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,2,3-thiadiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 434.1 (calculated forC₂₃H₂₃N₅O₂S, 433.54) 3071-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(isoxazol-5-ylcarbonyl)piperazine MS m/z (M + H⁺) 417.2 (calculated for C₂₄H₂₄N₄O₃,416.48) 308 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,2,5-oxadiazol-3-ylcarbonyl)piperazine MS m/z (M + H⁺) 418.2 (calculated forC₂₃H₂₃N₅O₃, 417.47) 3095-({4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)thiophene-3-carbonitrile MS m/z (M + H⁺) 457.2 (calculatedfor C₂₆H₂₄N₄O₂S, 456.57) 3101-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(isothiazol-5-ylcarbonyl)piperazine ¹H NMR (400 MHz, MeOD): δ 8.44 (s, 1H), 7.65 (s,4H), 7.53-7.58 (m, 2H), 7.47 (d, J = 1.71 Hz, 1H), 7.34-7.40 (m, 2H),7.26-7.32 (m, 1H), 4.49-4.60 (m, 1H), 4.37-4.49 (m, 1H), 4.27-4.37 (m,1H), 4.15-4.27 (m, 1H), 3.72-3.88 (m, 5H), 2.92-3.02 (m, 4H); MS m/z(M + H⁺) 433.2 (calculated for C₂₄H₂₄N₄O₂S, 432.55) 3111-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1H-pyrrol-3-ylcarbonyl)piperazine ¹H NMR (400 MHz, MeOD): δ 7.66 (s, 4H), 7.56-7.59(m, 1H), 7.54-7.56 (m, 1H), 7.35-7.41 (m, 2H), 7.26-7.33 (m, 1H),7.08-7.15 (m, 1H), 6.64-6.75 (m, 1H), 6.24-6.31 (m, 1H), 4.54-4.64 (m,1H), 4.43-4.51 (m, 1H), 4.32-4 .41 (m, 1H), 4.20-4.28 (m, 1H), 3.85-3.97(m, 5H), 3.06 (br. s., 4H); MS m/z (M + H⁺) 415.2 (calculated forC₂₅H₂₆N₄O₂, 414.51) 3121-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5-chlorofuran-2-yl)carbonyl]piperazine ¹H NMR (400 MHz, MeOD): δ 7.66 (s,4H), 7.54-7.59 (m, 2H), 7.38 (d, J = 7.58 Hz, 2H), 7.26-7.33 (m, 1H),7.05 (d, J = 3.67 Hz, 1H), 6.42 (d, J = 3.42 Hz, 1H), 4.50-4.63 (m, 1H),4.40-4.48 (m, 1H), 4.28-4.39 (m, 1H), 4.17-4.28 (m, 1H), 3.87-3.97 (m,4H), 3.78-3.87 (m, 1H), 2.97-3.07 (m, 4H); MS m/z (M + H⁺) 450.1(calculated for C₂₅H₂₄ClN₃O₃, 449.94) 480N-[4-({4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-l,3-thiazol-2-yl]acetamide MS m/z (M + H⁺) 490.2 14782-({4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)pyrimidine MS m/z (M + H⁺) 428.0 13981-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(cyclopentylcarbonyl)piperazine MS m/z (M + H⁺) 418.2 14651-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5-methylisoxazol-3-yl)carbonyl]piperazine MS m/z (M + H⁺) 431.3 12581-[1-(1,3-Oxazol-4-ylcarbonyl)azetidin-3-yl]-4-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}piperazine MS m/z (M + H⁺) 485.01262 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(isoxazol-3-ylcarbonyl)piperazine MS m/z (M + H⁺) 417.1 12221-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-oxazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 417.0 12691-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1H-1,2,3-triazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 417.0 12561-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(2,2-difluorocyclopropyl)carbonyl]piperazine MS m/z (M + H⁺) 426.0 13101-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1H-pyrazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 416.2 11401-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(furan-3-ylcarbonyl)piperazine MS m/z (M + H⁺) 416.2 12321-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(cyclobutylcarbonyl)piperazine MS m/z (M + H⁺) 404.2 13083-({4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 465.3 13241-(1H-Pyrrol-3-ylcarbonyl)-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 481.0 1325 1-(1H-Pyrrol-2-ylcarbonyl)-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 483.1 186-A1-[(D₅)Phenylcarbonyl]-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 499.4 11691-(1,3-Oxazol-5-ylcarbonyl)-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 485.0 1335 1-[(5-Bromofuran-2-yl)carbonyl]-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 560.0/562.0 1087 1-[(4-Bromothiophen-2-yl)carbonyl]-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 576.0/578.0 1078 1-[(5-Chlorofuran-2-yl)carbonyl]-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 518.2 1118 1-(Isoxazol-5-ylcarbonyl)-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 485.1 1336 1-[(5-Fluorothiophen-2-yl)carbonyl]-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 519.2 1145 1-(Isoxazol-3-ylcarbonyl)-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 485.2 1143 1-[(5-Chlorothiophen-2-yl)carbonyl]-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 535.2 1085 1-(1,3-Oxazol-2-ylcarbonyl)-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 485.1 1112 1-[(2,2-Difluorocyclopropyl)carbonyl]-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 494.2 1094 1-(1,3-Oxazol-4-ylcarbonyl)-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 485.2 10571-(Cyclopropylcarbonyl)-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 458.3 12171-[(2-Methyl-l,3-thiazol-4-yl)carbonyl]-4-(1-{[3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 516.3 14235-[(3-{4-[(5-Chlorothiophen-2-yl)carbonyl]piperazin-1-yl}azetidin-1-yl)carbonyl]-1-(4-fluorophenyl)-1H-indole MS m/z (M + H⁺)523.2 1424 1-(4-Fluorophenyl)-5-[(3-{4-[(3-fluorophenyl)carbonyl]piperazin-1-yl}azetidin-1- yl)carbonyl]-1H-indoleMS m/z (M + H⁺) 501.2 14255-[(3-{4-[(5-Chlorofuran-2-yl)carbonyl]piperazin-1-yl}azetidin-1-yl)carbonyl]-1-(4-fluorophenyl)-1H-indole MS m/z (M + H⁺)507.1 1426 1-(4-Fluorophenyl)-5-({3-[4-(1,3-oxazol-2-ylcarbonyl)piperazin-1-yl] azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 474.1 567-A 1-(4-Fluorophenyl)-5-[(3-{4-[(~2~H_5_)phenylcarbonyl]piperazin-1-yl} azetidin-1- yl)carbonyl]-lH-indole MS m/z (M + H⁺) 488.1 14271-(4-Fluorophenyl)-5-[(3-{4-[(5-fluorothiophen-2-yl)carbonyl]piperazin-1-yl}azetidin-1-yl)carbonyl]-1H-indole MS m/z (M +H⁺) 507.1 1428 1-(4-Fluorophenyl)-5-({3-[4-(1,3-oxazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 474.1 1429 1-(4-Fluorophenyl)-5-({3-[4-(1,3-oxazol-5-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 474.1

Example 9

A. 4-(Thiazole-2-carbonyl)-piperazine-1-carboxylic acid tert-butylester, 9a

To a solution of compound 5c (2.0 g, 15.50 mmol), compound 1a (3.2 g,17.20 mmol), and Et₃N (8.6 mL, 61.2 mmol) in CH₂Cl₂ (100 mL) was addedHATU (6.5 g, 17.1 mmol). The reaction mixture was stirred at roomtemperature for 18 h. The mixture was then diluted with CH₂Cl₂ andwashed with aq. NaHCO₃. The organic phase was dried over Na₂SO₄,filtered, and concentrated. Purification by flash column chromatography(silica gel, 30% EtOAc/heptane) gave compound 9a (4.0 g).

B. Piperazin-1-yl-thiazol-2-yl-methanone trifluoroacetic acid salt, 9b

To a solution of compound 9a (3.5 g, 11.78 mmol) in CH₂Cl₂ (40 mL) wasadded TFA (10 mL). The reaction mixture was stirred at room temperaturefor 2 h. It was then concentrated to give compound 9b, which was used inthe next reaction without further purification.

C. 3-[4-(Thiazole-2-carbonyl)-piperazin-1-yl]-azetidine-1-carboxylicacid tert-butyl ester, 7c

To a solution of compound 9b (11.78 mmol) and compound 4a (2.2 g, 12.87mmol) in 1,2-DCE (35 mL) and acetic acid (2 mL) was added Na(OAc)₃BH(2.75 g, 12.97 mmol). The reaction was stirred at room temperature for 5h. To the reaction mixture was added aq. NaHCO₃, and the resultantmixture was extracted with CH₂Cl₂. The organic layer was dried overNa₂SO₄ and concentrated. Purification by flash column chromatography(silica gel, 80% EtOAc/heptane) gave compound 7c (3.78 g).

D. (4-Azetidin-3-yl-piperazin-1-yl)-thiazol-2-yl-methanone, 5e

To a solution of compound 7c (1.2 g, 3.41 mmol) in CH₂Cl₂ (12 mL) wasadded TFA (3 mL). The reaction mixture was stirred at room temperaturefor 4.5 h, concentrated, and to the resulting residue was added aq.NaHCO₃. The mixture was extracted with 2% MeOH/CH₂Cl₂ (3×). The organicsolution was dried over Na₂SO₄ and concentrated to give compound 5e,which was used in the next reaction without further purification.

D.1-{1-[(5-Bromonaphthalen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 313

To a solution of compound 5e (63 mg, 0.25 mmol), compound 9c (95 mg,0.38 mmol), and Et₃N (0.14 mL, 1.01 mmol) in CH₂Cl₂ (3 mL) was addedHATU (143 mg, 0.38 mmol). The reaction mixture was stirred at roomtemperature for 18 h, then diluted with diethyl ether and washed withaq. NaHCO₃ and aq. NaCl. The organic layer was dried over Na₂SO₄ andconcentrated. Purification by flash column chromatography (silica gel,3% MeOH/CH₂Cl₂) gave compound 313. ¹H NMR (400 MHz, CD₃OD): δ 8.28 (d,J=9 Hz, 1H), 8.14 (d, J=1.6 Hz, 1H), 7.88-7.85 (m, 3H), 7.81 (d, J=8.4Hz, 1H), 7.54 (d, J=3 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 4.53 (bs, 1H),4.45 (bs, 1H), 4.34 (m, 2H), 4.26 (m, 1H), 4.16 (m, 1H), 3.95-3.80 (m,2H), 3.28 (m, 1H), 2.60-2.40 (m, 4H). MS m/z (M+H⁺) 485/487.

Following the procedure described above for Example 9 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 3146-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-[4-(trifluoromethyl)phenyl]-1,3-benzoxazole ¹H NMR (400 MHz, CD₃OD): δ 8.40 (d, J = 7.8 Hz, 1H),7.95 (s, 1H), 7.88 (d, J = 3 Hz, 1H), 7.83-7.80 (m, 2H), 7.69 (d, J = 8Hz, 1H), 7.55 (d, J = 3 Hz, 1H), 4.53 (m, 1H), 4.45-4.25 (m, 4H), 4.16(m, 1H), 3.95-3.80 (m, 2H), 3.27 (m, 1H), 2.60-2.40 (m, 4H). MS m/z (M +H⁺) 542 315 6-Bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 475/477 3161-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[5-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (400 MHz,CD₃OD): δ 8.13 (s, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 3 Hz,1H), 7.75 (s, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 3 Hz, 1H),4.62-4.40 (m, 4H), 4.31 (m, 1H), 4.16 (m, 1H), 3.35 (m, 1H), 2.60-2.40(m, 4H). MS m/z (M + H⁺) 481 3172-Phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole ¹H NMR (400 MHz, CD₃OD): δ8.26 (m, 2H), 8.00 (s, 1H), 7.88 (d, J = 3 Hz, 1H), 7.76 (d, J = 8.6 Hz,1H), 7.63 (d, J = 8.6 Hz, 1H), 7.60-7.52 (m, 4H), 4.60-4.40 (m, 2H),4.38 (m,1H), 4.28 (m, 2H), 4.15 (m, 1H), 3.86 (m, 2H), 3.27 (m, 1H),2.50 (m, 4H). MS m/z (M + H⁺) 474 3182-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole ¹H NMR (400 MHz, CD₃OD): δ8.28 (m, 2H), 7.92 (s, 1H), 7.88 (d, J = 3.2 Hz, 1H), 7.79 (d, J = 8 Hz,1H), 7.66 (d, J = 8 Hz, 1H), 4.60-4.20 (m, 5H), 4.15 (m, 1H), 3.86 (m,2H), 3.28 (m, 1H), 2.50 (m, 4H). MS m/z (M + H⁺) 474 319 tert-Butyl6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3,4-dihydroisoquinoline-2(1H)- carboxylate,¹H NMR (CDCl₃): δ 7.44-7.39 (m, 7H), 7.13 (d, J = 0.02, 1H), 4.59 (s,2H), 4.27 (m, 2H), 4.15 (m, 1H), 4.06 (m, 1H), 3.90 (m, 1H), 3.74 (m,1H), 3.65 (m, 2H), 3.46 (m, 2H), 3.22 (m, 1H), 2.85 (m, 2H), 2.27-2.23(m, 4H), 1.49 (s, 9H) MS m/z 405.0 (M-Boc), 449.0 (M-Bu-t), 527 (M +Na), 1009.2 (2M + H) 3201-{1-[(4,5-Dibromothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 511.8, 513.8, 514.8 3211-{1-[(5-Benzylthiophen-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine, ¹H NMR (CDCl₃): δ 7.42-7.38 (m, 5H),7.33-7.29 (m, 3H), 7.26 (m, 3H), 6.78 (d, J = 0.01, 1H), 4.41 (m, 1H),4.24 (m, 2H), 4.13 (s, 2H), 4.03 (m, 1H), 3.92-3.74 (m, 2H), 3.47 (m,2H), 3.24 (m, 1H), 2.42-2.29 (m, 4H) MS m/z (M + H⁺) 446.6 3221-{1-[(5-Bromothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 432.4, 434.4 832l-Cyclohexyl-2-methyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 493.0 11981-(1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 615.0 6474-[4-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)piperidin-1-yl]benzonitrile MS m/z (M + H⁺)465.1 1302 1-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}carbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 491.1 12611-{1-[(1,5-Diphenyl-1H-pyrazol-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 499.2 6541-[1-(Phenoxathiin-2-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 479.1 7679-Methyl-3-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-9H-carbazole MS m/z (M + H⁺) 460.0 8221-(1-{[4-(Phenylsulfonyl)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 497.1 8176-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3,4,9-tetrahydro-1H- carbazole MS m/z (M +H⁺) 450.1 775 N-Benzyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline MS m/z (M + H⁺) 462.3 713N-Benzyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline MS m/z (M + H⁺) 462.3 14133-Methyl-1-[4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]-1H-indole MS m/z (M + H⁺) 486.1 9185-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-indol-2-one MS m/z (M + H⁺)412.1 829 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3-dihydro-1H-indole ¹H NMR (400 MHz,CD₃OD): δ 7.99 (d, 1H), 7.89 (d, 1H), 7.57 (s, 1H), 7.52 (d, J = 8. 1Hz,1H), 7.03 (d, J = 8. 1 Hz, 1H), 4.28-4.90 (m, 6H), 4.01-4.22 (m, 3H),3.73 (t, J = 8.2 Hz, 2H), 3.37 (br. s., 4H), 3.19 (t, J = 8.2 Hz, 2H) MSm/z (M + H⁺) 398.1 1320 1-(4-Fluorophenyl)-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR (400MHz, CDCl₃): δ 7.88 (d, J = 3.2 Hz, 1H), 7.50-7.57 (m, 2H), 7.42-7.48(m, 2H), 7.38 (d, J = 3.2 Hz, 1H), 7.33 (d, J = 7.3 Hz, 1H), 7.18-7.26(m, 3H), 6.99 (d, J = 3.2 Hz, 1H), 4.05-4.63 (m, 6H), 3.75-3.99 (m, 2H),3.22- 3.32 (m, 1H), 2.37-2.62 (m, 4H) MS m/z (M + H⁺) 490.1 8061-{1-[(4-Bromothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H) 440.0, (M + 2⁺)442.0 718 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)-1,3- benzothiazole MS m/z482 (M + H⁺) 1088 1-(4-Fluorophenyl)-3-methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR(CDCl₃,400 MHz): δ 7.98 (s, 1H), 7.88 (d, J = 3.1 Hz, 1H), 7.47-7.58 (m,2 H), 7.38-7.47 (m, 3 H), 7.16- 7.26 (m, 2 H), 7.12 (s, 1H), 4.47-4.64(m, 1H), 4.38 (br. s., 4 H), 4.07-4.19 (m, 1H), 3.74-3.97 (m, 2 H),3.17-3.33 (m, 1H), 2.50 (t, J = 4.9 Hz, 4 H), 2.39 (s, 3 H). MS m/z 504(M + H⁺) 1131 2-(3-Fluorophenyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzothiazole MSm/z 508 (M + H⁺) 1054 3-Methyl-1-phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z 486(M + H⁺) 1152 3-Methyl-1-phenyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z 486(M + H⁺) 1367 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(3,4,5-trifluorophenyl)-1H- indole MS m/z526 (M + H⁺) 1106 1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole ^(′)H NMR(CDCl₃, 400 MHz): δ 8.27 (s, 1H), 8.12 (s, 1H), 7.88 (br. s., 1H),7.67-7.85 (m, 2 H), 7.42-7.67 (m, 3 H), 7.36 (q, J = 8.7 Hz, 1H),4.49-4.62 (m, 1H), 4.20-4.48 (m, 4 H), 4.05-4.20 (m, 1H), 3.84 (br. s.,2 H), 3.20-3.38 (m, 1H), 2.51 (m, 4 H). MS m/z 509 (M + H⁺) 11291-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole MS m/z509 (M + H⁺) 1055 5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(3,4,5-trifluorophenyl)-1H- indole MS m/z526 (M + H⁺) 1077 2-(3,4-Difluorophenyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MSm/z 510 (M + H⁺) 1178 2-(3,4-Difluorophenyl)-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MSm/z 510 (M + H⁺) 13681-(3-Fluorophenyl)-3-methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z 504(M + H⁺) 1369 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4- (trifluoromethoxy)phenyl]-1H-indole MSm/z 556 (M + H⁺) 1370 5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4- (trifluoromethoxy)phenyl]-1H-indole MSm/z 556 (M + H⁺) 1371 1-(3,5-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z 508(M + H⁺) 1068 3-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[3- (trifluoromethoxy)phenyl]-1H-indole MSm/z 570 (M + H⁺) 1110 1-(3-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole MS m/z491 (M + H⁺) 1372 l-(4-Chloro-3-fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z 523(M + H⁺) 1373 1-(2,5-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z 508(M + H⁺) 1090 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole MS m/z491 (M + H⁺) 1492 1-{1-[(5-Bromo-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 455, 457 8121-{1-[(5-Bromo-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺)468, 470 6817-Bromo-1-methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 488, 490 723 1-{1-[(5-Bromo-4-methylthiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 455, 457745 1-{1-[(4-Bromo-5-methylthiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 475, 4771224 1-(4-Fluorophenyl)-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 490 1226 1-(3-Fluorophenyl)-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 490 1279 1-(3-Fluorophenyl)-3-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 490 1295 1-(4-Fluorophenyl)-3-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 490 1275 2-Phenyl-6-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 474.1 6067-(Biphenyl-4-ylcarbonyl)-4-[1-(phenylcarbonyl)azetidin-3-yl]-4,7-diazaspiro[2.5]octane MS m/z (M + H⁺) 452.4 12867-(Biphenyl-4-ylcarbonyl)-4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]-4,7-diazaspiro[2.5]octane MS m/z (M + H⁺)459.3 1499 4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-7-(phenylcarbonyl)-4,7-diazaspiro[2.5]octane MS m/z (M + H⁺) 272 8205-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indazole ¹H NMR (400 MHz, CDCl₃): δ3.34-3.48 (m, 1 H), 3.89 (br. s., 3 H), 4.08-4.66 (m, 8 H), 7.55 (d, J =8.8 Hz, 1 H), 7.62 (d, J = 3.2 Hz, 1 H), 7.66 (dd, J = 8.8, 1.5 Hz, 1H), 7.89 (d, J = 3.2 Hz, 1 H), 8.04 (s, 1 H), 8.09 (s, 2 H) MS m/z (M +H⁺) 397.2 1277 1-(4-Fluorophenyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-pyrrolo[3,2-b]pyridine ¹H NMR (400 MHz, CDCl₃): δ 2.92-3.16 (m, 4 H),3.76 (t, J = 5.3 Hz, 1 H), 4.06 (br. s., 2 H), 4.39 (br. s., 1 H), 4.49-4.93 (m, 5 H), 7.23 (d, J = 3.2 Hz, 1 H), 7.30-7.38 (m, 2 H), 7.44-7.54(m, 2 H), 7.60 (d, J = 3.2 Hz, 1 H), 7.89 (d, J = 3.2 Hz, 1 H), 7.97 (d,J = 3.2 Hz, 1 H), 8.63 (s, 1 H), 9.12 (s, 1 H) MS m/z (M + H⁺) 491.21056 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-pyrrolo[2,3-b]pyridine ¹H NMR (400 MHz, CDCl₃): δ 3.75 (s, 1 H), 4.11(br. s., 2 H), 4.32-5.02 (m, 10 H), 6.75 (d, J = 3.6 Hz, 1 H), 7.23 (d,J = 8.9 Hz, 2 H), 7.53 (d, J = 3.7 Hz, 1 H), 7.61 (d, J = 3.2 Hz, 1 H),7.65 (m, J = 9.0, 4.7 Hz, 2 H), 7.89 (d, J = 3.2 Hz, 1 H), 8.33 (d, J =2.0 Hz, 1 H), 8.60 (d, J = 1.7 Hz, 1 H) MS m/z (M + H⁺) 491.2 11531-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-pyrrolo[3,2-b]pyridine ¹H NMR (400 MHz, CDCl₃): δ 3.83-4.34 (m, 9 H),4.41- 4.70 (m, 2 H), 5.14 (d, J = 5.8 Hz, 2 H), 6.90 (br. s., 1 H), 7.28(d, J = 8.2 Hz, 2 H), 7.38-7.51 (m, 2 H), 7.62 (d, J = 3.2 Hz, 1 H),7.65 (d, J = 2.9 Hz, 1 H), 7.85 (d, J = 8.6 Hz, 1 H), 7.90 (d, J = 3.2Hz, 1 H), 7.99 (d, J = 8.6 Hz, 1 H) MS m/z (M + H⁺) 491.2 13061-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)-2-(trifluoromethyl)piperazine ¹H NMR (400 MHz, CD₃OD): δ2.14 (dd, J = 22.7, 10.5 Hz, 1 H), 2.43 (dd, J = 41.6, 11. 7 Hz, 1 H),2.87-3.18 (m, 1 H), 3.18-3.44 (m, 1.5 H), 3.58-3.81 (m, 0.5 H), 3.95-4.17 (m, 1 H), 4.18-4.40 (m, 2 H), 4.49 (m, 1.5 H), 5.43 (d, J = 26.4Hz, 1 H), 6.95 (br. s., 0.5 H), 7.33-7.43 (m, 1 H), 7.43-7.51 (m, 2 H),7.66 (d, J = 7.6 Hz, 2 H), 7.70- 7.80 (m, 4 H), 7.88 (br. s., 1 H),7.93-8.03 (m, 1 H) MS m/z (M + H⁺) 501.1 8565-({3-[4-(1H-Pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 378 1116 2:1 mixture of 2components: Major: 1-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 575.1 Minor:1-[2-Fluoro-5-(trifluoromethyl)pyridin-3-yl]-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 559.0 12332-Phenyl-6-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺)) 474.1

Example 9b

1-[1-[(6-Bromonaphthalen-2-yl)carbonyl]azetidin-3-yl]-4-(phenylcarbonyl)piperazine,Cpd 118

The title compound was prepared in an analogous manner to thepreparation of Cpd 313 of Example 9, except commercially availableN-benzoylpiperazine was used as starting material, instead ofintermediate 9b. MS 478/480 (M+H⁺).

Following the procedure described above for Example 9b and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 1197-Bromo-3-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M + H⁺) 479/481 1201-{1-[(5-Chloro-3-methyl-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine ¹H NMR (400 MHz,CD₃OD): δ 7.74 (d, J = 2 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.43-7.36(m, 6H), 4.28 (m, 2H), 4.20-4.00 (m, 2H), 4.00-3.70 (m, 2H), 3.48 (m,2H), 3.24 (m, 1H), 2.58 (s, 3H), 2.50-2.20 (m, 4H). MS m/z (M + H⁺) 454121 2-Phenyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 467 1222-Methyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole MS m/z (M + H⁺) 421 1232-(4-Methoxyphenyl)-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 497 1241-(Phenylcarbonyl)-4-(1-{[5-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 474125 1-{1-[(6-Bromo-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 484/486 1265-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole ¹H NMR (400 MHz,CD₃OD): δ 8.00 (s, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.6 Hz,2H), 7.58 (s, 2H), 7.40 (m, 6H), 6.78 (d, J = 3.5 Hz, 1H), 4.37 (m, 1H),4.30-4.20 (m, 2H), 4.11 (m, 1H), 3.60-3.40 (m, 2H), 3.24 (m, 1H),2.50-2.20 (m, 4H). MS m/z (M + H⁺) 533 1272-(4-Chlorophenyl)-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 500 1281-Phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole ¹H NMR (400 MHz, CD₃OD): δ 7.98 (s, 1H),7.56-7.37 (m, 13H), 6.73 (d, J = 3.2 Hz, 1H), 4.37 (m, 1H), 4.29-4.20(m, 2H), 4.10 (bs, 1H), 3.90 (bs, 1H), 3.74 (bs, 1H), 3.38 (m, 2H), 3.23(m, 1H), 2.50-2.20 (m, 4H). MS m/z (M + H⁺) 465 1291-[3-(Trifluoromethyl)phenyl]-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR(400 MHz, CD₃OD): δ 8.00 (s, 1H), 7.76 (s, 1H), 7.72-7.64 (m, 3H),7.58-7.50 (m, 2H), 7.41 (m, 6 H), 6.78 (d, J = 3 Hz, 1H), 4.37 (m, 1H),4.30-4.20 (m, 2H), 4.11 (m, 1H), 3.91 (bs, 1H), 3.75 (bs, 1H), 3.48 (m,2H), 3.25 (m, 1H), 2.55-2.20 (m, 4H). MS m/z (M + H⁺) 533 1305-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(phenylsulfonyl)-1H-indole MS m/z (M + H⁺) 529 1316-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-[3-(trifluoromethyl)phenyl]-1,3-benzoxazole ¹H NMR (400MHz, CD₃OD): δ 8.54 (s, 1H), 8.45 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 1.2Hz, 1H), 7.82 (m, 2H), 7.69 (m, 2H), 7.41 (m, 5H), 4.38 (m, 1H),4.32-4.22 (m, 2H), 4.12 (m, 1H), 3.90 (bs, 1H), 3.76 (bs, 1H), 3.50 (bs,2H), 3.27 (m, 1H), 2.50-2.20 (m, 4H). MS m/z (M + H⁺) 535 1322-Phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 467 6171-(4-Fluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indazole MS m/z 484 (M + H⁺) 5711-(3,4-Difluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole ¹H NMR (CDCl₃, 400 MHz): δ 7.99 (s,1 H), 7.53-7.63 (m, 1 H), 7.45-7.53 (m, 1 H), 7.16-7.45 (m, 9 H), 6.74(d, J = 3.1 Hz, 1 H), 4.37 (br. s., 1 H), 4.16-4.32 (m, 2 H), 4.11 (br.s., 1 H), 3.83-4.00 (m, 1 H), 3.65-3.83 (m, 1 H), 3.48 (br. s., 2 H),3.17-3.31 (m, 1 H), 2.44 (br. s., 4 H) MS m/z 501 (M + H⁺) 5841-(4-Fluorophenyl)-3-methyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z497 (M + H⁺) 5992-(3-Fluorophenyl)-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole MS m/z 501 (M + H⁺) 5831-(3-Fluorophenyl)-3-methyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z497 (M + H⁺) 577 3-Methyl-1-phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z 479 (M + H⁺) 5695-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(3,4,5-trifluorophenyl)-1H-indole MS m/z 519 (M + H⁺) 5735-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethoxy)phenyl]-1H-indole MS m/z 549 (M +H⁺) 580 1-(3,5-Difluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z 501 (M + H⁺) 5681-(4-Chloro-3-fluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z517 (M + H⁺) 5781-(2,5-Difluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z 501 (M + H⁺) 5901-(3,4-Difluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indazole MS m/z 502 (M + H⁺)

Example 9c

Following the procedure described above for Example 1b, with theexception of using 1,10-phenanthroline instead oftrans-N,N′-dimethylcyclohexane-1,2-diamine as a ligand in step K, andsubstituting the appropriate reagents, starting materials, andpurification methods known to those skilled in the art, the followingintermediate compound:

Following the procedure described above for Example 9, step D, andsubstituting the appropriate reagents, starting materials, andpurification methods known to those skilled in the art, the followingcompounds of the present invention were prepared:

Cpd Cpd Name and Data 1375 2-Methyl-4-[5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile MS m/z (M + H⁺) 511 14212-Methyl-4-[5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile MS m/z (M + H⁺) 511 5662-Methyl-4-[5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1- yl]benzonitrile MS m/z (M + H⁺)504

Example 9d

E. Methyl 1-(4-cyanophenyl)-indole-5-carboxylate, 9d

was prepared according to Example 1a step H.

F. 1-(4-cyanophenyl)-indole-5-carboxylic acid, 9e and1-(4-carbamoyl-phenyl)-indole-5-carboxylic acid, 9f

A mixture of methyl 1-(4-cyanophenyl)-indole-5-carboxylate, 9d (156 mg,0.57 mmol) and LiOH (54 mg, 2.26 mmol) in THF (4 mL) and H₂O (2 mL) wasstirred at room temperature for 4 days. Aqueous 10% HCl solution wasadded to the reaction mixture to adjust pH=3˜4. The resulting mixturewas extracted with EtOAc (2×). The organic solution was washed with aq.NaCl, dried over Na₂SO₄ and concentrated. Purification by flash columnchromatography (silica gel, 4-8% MeOH/CH₂Cl₂) gave 9e (75 mg), followedby 9f (27 mg).

Following the procedure described above for Example 9d and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Following the procedure described above for Example 9, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 11594-[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile MS m/z (M + H⁺)497 1171 4-[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzamide MS m/z (M + H⁺) 5151133 4-[5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile MS m/z (M + H⁺)497 1109 2-[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile MS m/z (M + H⁺)497 1182 2-[5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile MS m/z (M + H⁺)497 1113 3-[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile MS m/z (M + H⁺)497 1177 3-[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzamide MS m/z (M + H⁺) 515

Following the procedure described above for Example 9b, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 582 4-[5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1- yl]benzonitrile MS m/z (M + H⁺)490 588 2-[5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1- yl]benzonitrile MS m/z (M + H⁺)490 594 3-[5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzamide MS m/z (M + H⁺) 508

Example 9e

G. Ethyl 1-(3-trifluoromethyl-phenyl)-1H-indazole-5-carboxylate, 91 andEthyl 1-(3-trifluoromethyl-phenyl)-1H-indazole-5-carboxylate, 9j

A mixture of ethyl 1H-Indazole-5-carboxylate 9g (150 mg, 0.79 mmol),1-bromo-3-trifluoromethylbenzene 9h (0.13 mL, 0.95 mmol), CuI (22.5 mg,0.12 mmol), trans-N, N′-dimethylcyclohexane-1,2-diamine (0.056 mL, 0.36mmol), and K₃PO₄ (0.37 g, 1.74 mmol) in toluene (1.5 mL) was heated at110° C. for 16 hours. The reaction mixture was diluted with CH₂Cl₂ andfiltered. The solution was concentrated and the residue was purified byflash column chromatography (silica gel, 10% EtOAc/heptane) to give 91(190 mg), followed by 9j (37 mg).

H. 1-(3-Trifluoromethyl-phenyl)-1H-indazole-5-carboxylic acid, 9k and1-(3-Trifluoromethyl-phenyl)-1H-indazole-5-carboxylic acid, 9l. 9k and9l

were prepared according to Example 1b Step L from 9l and 9jrespectively.

Following the procedure described above for Example 9e, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Following the procedure described above for Example 9, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 10805-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]- 1H-indazole MSm/z (M + H⁺) 541 1374 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[3- (trifluoromethoxy)phenyl]-1H-indazoleMS m/z (M + H⁺) 557 1376 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-[3- (trifluoromethoxy)phenyl]-2H-indazoleMS m/z (M + H⁺) 557 1419 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[3-(trifluoromethyl)phenyl]- 1H-indazole MSm/z (M + H⁺) 541 1420 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-[3-(trifluoromethyl)phenyl]- 2H-indazole MSm/z (M + H⁺) 541 1422 5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-[3- (trifluoromethoxy)phenyl]-2H-indazoleMS m/z (M + H⁺) 557

Following the procedure described above for Example 9b, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 5755-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H- indazole MS m/z (M + H⁺)534 576 5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[3-(trifluoromethoxy)phenyl]-1H- indazole MS m/z (M + H⁺)550

Example 9f

I. Methyl 1-(4-cyano-3-fluorophenyl)-indole-5-carboxylate, 9m

was prepared according to Example 9e step H.

J. Methyl 1-(4-cyano-3-methoxyphenyl)-indole-5-carboxylate, 9n

A solution of 95 mg (0.32 mmol) of compound 9m was combined with 120 mg(0.87 mmol) of K₂CO₃ in 8 mL of MeOH and heated at 75° C. for 5 h. Themixture was cooled, diluted with water, and extracted with CH₂Cl₂. Theorganic solution was concentrated to give 100 mg (100%) of 9n as a whitesolid.

K. 1-(4-cyano-3-methoxyphenyl)-indole-5-carboxylic acid, 93 and1-(4-carbamoyl-phenyl)-indole-5-carboxylic acid, 9o

A mixture of 100 mg (0.33 mmol) of compound 9m and LiOH (31 mg, 1.3mmol) in THF (4 mL) and H₂O (2 mL) was stirred at room temperature for 3days. Aqueous 10% HCl solution was added to the reaction mixture toadjust pH=3˜4. The resulting mixture was extracted with EtOAc (2×). Theorganic solution was washed with aq. NaCl, dried over Na₂SO₄ andconcentrated to give 90 mg (94%) of compound 90 as a white solid.

Following the procedure described above for Example 9, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 1115 2-Methoxy-4-[5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile MS m/z (M + H⁺) 527 6332-Methoxy-4-[5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile MS m/z (M + H⁺)520

Example 9g

L. Ethyl 2-(thiazol-2-yl)benzo[d]thiazole-6-carboxylate, 9q

A mixture of ethyl 2-bromo-benzothiazole-6-carboxylate 1w (150 mg, 0.53mmol), 2-tributylstannylthiazole 9p (0.25 mL, 0.79 mmol), and Pd(PPh₃)₄(30 mg, 0.03 mmol) in dioxane (2 mL) was heated at 130° C. for 30 minunder microwave. The reaction mixture was diluted with CH₂Cl₂, washedwith aq. NaHCO₃, dried over Na₂SO₄, and concentrated. Purification byflash column chromatography (silica gel, 10% EtOAc/heptane) gave 9q (130mg).

M. 2-(Thiazol-2-yl)benzo[d]thiazole-6-carboxylic acid, 9r

Ethyl 2-phenyl-benzothiazole-6-carboxylate 9q (130 mg, 0.45 mmol) wasstirred with LiOH (43 mg, 1.8 mmol) in THF (4 mL) and H₂O (2 mL) for 6h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3-4.The resulting mixture was extracted with EtOAc (2×). The organicsolution was washed with aq. NaCl, dried over Na₂SO₄ and concentrated togive 9r (110 mg).

Following the procedure described above for Example 9g and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Following the procedure described above for Example 9, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 1210 2-(1,3-Thiazol-2-yl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzothiazole MSm/z (M + H⁺) 497 1165 2-Pyridin-2-yl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzothiazole MSm/z (M + H⁺) 491

Example 9h

N. Methyl2-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylate, 9u

A mixture of methyl 1,2,3,4-tetrahydroisoquinoline-8-carboxylate 9s (100mg, 0.44 mmol), 2-bromopyrimidine 9t (77 nm, 0.48 mmol), and Et₃N (0.13mL, 0.92 mmol) in acetonitrile (5 mL) was stirred at room temperatureovernight. The reaction mixture was worked up to give crude 9v (187 mg).

M. 2-(Pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid,9v

Compound 9u (187 mg, 0.44 mmol) was refluxed with 3N aqueous NaOH (0.25mL mg, 0.75 mmol) in THF (6 mL) overnight. Concentrated HCl solution wasadded to the mixture to adjust pH to 3-4. The resulting mixture wasconcentrated to give 9v (350 mg) as the tris-HCl salt.

Following the procedure described above for Example 9, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compound of the presentinvention was prepared:

Cpd Cpd Name and Data 2-Pyrimidin-2-yl-8-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 490.1

Example 91

N. Methyl 3-Amino-2-benzoylamino-benzoate, 9y

To a solution of 500 mg (3.0 mmol) of methyl 2,3-diaminobenzoate 9w and730 mg (6.0 mmol) of benzoic acid 9x in 8 mL of CH₂Cl₂ was added 620 mg(3.0 mmol) of dicyclohexylcarbodiimide (DCC) and 4 mg (0.033 mmol) ofDMAP. The reaction was stirred overnight and the solid was filtered off.The solid was purified by flash column chromoatography (silica gel,10-30% gradient of EtOAc in heptanes) to give 220 mg (27%) of methyl3-Amino-2-benzoylamino-benzoate, 9y. MS m/z (M+H⁺) 271.2

O. Methyl 2-phenyl-1H-benzo[d]imidazole-7-carboxylate, 9z

A solution of 810 mg (3.0 mmol) of methyl3-amino-2-benzoylamino-benzoate 9y in 15 ml acetic acid was heated to125° C. for 1.5 h. The reaction was cooled and poured into ice/water.The aqueous layer was made basic with NaHCO₃ and extracted with CH₂Cl₂.The organic solution was dried over Na₂SO₄ and evaporated to give 540 mg(71%) of methyl 2-phenyl-1H-benzo[d]imidazole-7-carboxylate, 9z. MS m/z(M+H⁺) 253.2

P. Phenyl-1H-benzo[d]imidazole-7-carboxylic acid, 9aa

A mixture of 540 mg (2.1 mmol) of methyl2-phenyl-1H-benzo[d]imidazole-7-carboxylate 9z and 3 mL (9 mmol) of 3Naqueous NaOH was refluxed in 8 mL of THF overnight. After cooling, themixture was poured into ice water and acidified with conc. HCl. Theresulting solid was filtered and dried to give 440 mg (86%) ofphenyl-1H-benzo[d]imidazole-7-carboxylic acid, 9aa. MS m/z (M+H⁺) 238.9.

Following the procedure described above for Example 91, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Following the procedure described above for Example 9, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 6082-(2-Chlorophenyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 500.3 6092-(3-Fluorophenyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 484.3 6022-(4-Fluorophenyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 484.3 6072-(4-Chlorophenyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 500.3 6012-Phenyl-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 466.3 13892-(3-Chlorophenyl)-7-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 507.2 13992-Furan-2-yl-7-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 463.2 13902-Phenyl-7-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 473.2 13872-Pyridin-4-yl-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 474.3 12522-Furan-2-yl-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 463.3 12552-Phenyl-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 463.3 13882-(2-Fluorophenyl)-4-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 491.2 1391 2-(3-Fluorophenyl)-4-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 491.2 1393 2-(4-Fluorophenyl)-4-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 491.2 1394 2-(2-Chlorophenyl)-4-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 507.2 1290 2-(4-Chlorophenyl)-4-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 507.2 9802-Benzyl-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 487 9892-(2-Fluorobenzyl)-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 505.2 990 2-(3-Fluorobenzyl)-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 505.2 991 2-(4-Chlorobenzyl)-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 521.2 1461 2-(Pyridin-4-ylmethyl)-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 488.2

Example 9j

Q. Methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9dd

A solution of 1.0 g (4.9 mmol) of methyl 2-amino-3-hydroxybenzoate 9bb,1.03 g (7.4 mmol) of 4-fluorobenzoic acid 9 cc, 10 mL DMF and 2.9 mL(20.6 mmol) of TEA were placed into a flask and stiffed for 10 min HATU(7.4 mmol, 2.8 g) was added and the reaction was stiffed overnight. Thereaction mixture was poured into water and extracted with EtOAc. Theorganics were washed with water and brine and the solvent was evaporatedto give 1.2 g of crude product, methyl2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9dd, which was usedwithout purification. MS m/z (M+H⁺) 290.1.

R. Methyl 2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylate, 9ee

Methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate 9dd (7.4 mmol, 1.2 gcrude) and 1.3 g (7.5 mmol) of p-toluenesulfonic acid was refluxed in 10mL of xylene overnight. After cooling saturated NaHCO₃ was added and theresulting mixture was extracted with EtOAc. The organic solvent wasevaporated to give 1.1 g (55%) of methyl2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylate, 9ee. MS m/z (M+H⁺)272.0.

S. 2-(4-Fluorophenyl)-benzo[d]oxazole-4-carboxylic acid, 9ff

A mixture of 1.1 g (4.0 mmol) methyl2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylate 9ee and 3.7 mL of 3Naqueous NaOH in 10 mL of THF was refluxed overnight. After cooling thereaction mixture was poured into water and acidified with conc. HCl. Theresulting solid was filtered and dried to give 830 mg (79%) of2-(4-fluorophenyl)-benzo[d]oxazole-4-carboxylic acid, 9ff. MS m/z (M+H⁺)258.1.

Following the procedure described above for Example 9j, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Following the procedure described above for Example 9, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 11542-Phenyl-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole ¹H NMR (400 MHz, CDCl₃): δ8.32 (m, 2H); 7.95 (m, 2H); 7.85 (m, 1H); 7.71-7.49 (m, 5H); 4.85-4.44(bm, 3H); 4.15-3.91 (bm, 3H); 3.23 (bm, 3H) MS m/z (M + H⁺) 474.2 12542-(3-Fluorophenyl)-7-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MSm/z (M + H⁺) 492.1 1282 2-(4-Fluorophenyl)-7-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MSm/z (M + H⁺) 492.1 1238 2-(3-Chlorophenyl)-7-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MSm/z (M + H⁺) 507.9 1380 2-(4-Chlorophenyl)-7-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole ¹HNMR (400 MHz, CDCl₃): δ 9.05 (bs, 1H); 8.3 (d, 2H); 8.2 (m, 1H); 7.95(d, 1H); 7.66 (t, 3H); 7.44 (t, 1H); 4.69-4.52 (m, 1H); 4.44 (m, 2H);4.10 (bm, 2H); 3.20 (m, 4H). MS m/z (M + H⁺) 507.9 11902-Phenyl-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 474 11932-(2-Fluorophenyl)-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MSm/z (M + H⁺) 492.2 1257 2-(4-Fluorophenyl)-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MSm/z (M + H⁺) 492.2 1173 2-(2-Chlorophenyl)-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MSm/z (M + H⁺) 508.2 1191 2-(3-Chlorophenyl)-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MSm/z (M + H⁺) 508.2 1220 2-(4-Chlorophenyl)-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MSm/z (M + H⁺) 508.9 12372-Phenyl-7-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 474.2 12512-Pyridin-3-yl-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 475.1

Example 10

A. 6-Trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride, 10b

To compound 10a (0.13 g, 0.53 mmol) in CH₂Cl₂ (5 mL) at room temperaturewas added (COCl)₂ (0.051 mL, 0.58 mmol), followed by 2 drops of DMF. Thereaction mixture was stirred at room temperature for 18 h. The reactionmixture was then concentrated to give compound 10b, which was used inthe next reaction without further purification.

B.1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine

To a solution of compound 5e (60 mg, 0.24 mmol) and Et₃N (0.08 mL, 0.58mmol) in CH₂Cl₂ (3 mL) at 0° C. was added a solution of compound 10b(0.53 mmol) in CH₂Cl₂ (1 mL). The reaction was slowly warmed up to roomtemperature over 4.5 h, diluted with CH₂Cl₂, and washed with aq. NaHCO₃.The organic layer was dried over Na₂SO₄ and concentrated. Purificationby flash column chromatography (silica gel, 3% MeOH/CH₂Cl₂) affordedcompound 323. ¹H NMR (400 MHz, CD₃OD): δ 8.15 (s, 1H), 7.94 (d, J=8.6Hz, 1H), 7.89 (d, J=3 Hz, 1H), 7.74 (s, 1H), 7.62 (d, J=8.6 Hz, 1H),7.56 (d, J=3 Hz, 1H), 4.60 (m, 2H), 4.45 (m, 2H), 4.30 (m, 1H), 4.16 (m,1H), 3.95-3.89 (m, 2H), 3.35 (m, 1H), 2.55 (bs, 4H). MS m/z (M+H⁺) 481.

Following the procedure described above for Example 10 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 3241-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹HNMR (400 MHz, CD₃OD): δ 8.13 (s, 1H), 8.01 (d, J = 8 Hz, 1H), 7.88 (d, J= 3 Hz, 1H), 7.73 (d, J = 8 Hz, 1H), 7.55 (d, J = 3 Hz, 1H), 4.53 (bs,1H), 4.46 (bs, 1H), 4.31 (m, 2H), 4.22 (m, 1H), 4.16 (m, 1H), 3.33 (m,1H), 2.60-2.40 (m, 4H). MS m/z (M + H⁺) 515 3251-(Phenylcarbonyl)-4-(1-{[6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (400 MHz,CD₃OD): δ 8.15 (s, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.73 (s, 1H), 7.62 (d,J = 8.6 Hz, 1H), 7.42 (m, 5H), 4.58 (m, 1H), 4.42 (m, 1H), 4.28 (m, 1H),4.12 (m, 1H), 3.93 (bs, 1H), 3.77 (bs, 1H), 3.51 (bs, 2H), 3.34 (m, 1H),2.60-2.30 (m, 4H). MS m/z (M + H⁺) 474 6863-Methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)thieno[2,3- b]pyridine MSm/z (M + H⁺) 496 7493-Methyl-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)thieno[2,3- b]pyridine MSm/z (M + H⁺) 496 8011-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)-2-(trifluoromethyl)piperazine MS m/z (M + H⁺) 583.0 8334-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-1-(1,3-thiazol-4-ylcarbonyl)-2-(trifluoromethyl)piperazine MS m/z (M + H⁺) 583.0 7781-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)-2-(trifluoromethyl)piperazine ¹H NMR (400 MHz, CD₃OD): δ 2.13 (d, J = 13.2Hz, 1 H), 2.41 (d, J = 47.2 Hz, 1 H), 2.8-3.3 (m, 2.5 H), 3.69 (d, J =13.7 Hz, 0.5 H), 3.98-4.42 (m, 4 H), 4.51 (t, J = 13.4 Hz, 0.5 H),5.27-5.54 (m, 1 H), 6.93 (br. s., 0.5 H), 7.83 (d, J = 8.6 Hz, 1 H),7.88 (br. s., 1 H), 7.97 (t, J = 6.8 Hz, 1 H), 8.11 (d, J = 8.8 Hz, 1H), 8.42 (s, 1 H) MS m/z (M + H⁺) 583.0

Example 10a

C. Methyl3-chloro-5-fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylate, 10dand methyl3-chloro-6-trifluoromethyl-7-fluoro-benzo[b]thiophene-2-carboxylate, 10e

A mixture of 3-fluoro-4-(trifluoromethyl)-cinnamic acid 10c (1.5 g, 6.4mmol), SOCl₂ (2.33 mL, 32 mmol), DMF (0.05 mL, 0.64 mmol), and pyridine(0.05 mL, 0.64 mmol) in chlorobenzene (5 mL) was heated to reflux for 24h. The reaction mixture was cooled to room temperature and concentrated.The resulting residue was dissolved in MeOH (50 mL) and stirred at roomtemperature for 16 h. The solution was concentrated, diluted with CH₂Cl₂and washed with H₂O. The organic solution was dried over Na₂SO₄ andconcentrated. Recrystallization with heptanes, followed by flash columnchromatography (silica gel, 2% EtOAc/heptane) gave 10d (580 mg) and 10e(380 mg).

D. 3-Chloro-5-fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylicacid, 10f

Methyl3-chloro-5-fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylate 10d(180 mg, 0.58 mmol) was stirred with LiOH (55 mg, 2.3 mmol) in THF (5mL) and H₂O (2.5 mL) for 4 h. Aqueous 1N HCl solution was added to themixture to adjust pH to 3-4. The resulting mixture was extracted withEtOAc (2×). The organic solution was washed with aq. NaCl, dried overNa₂SO₄ and concentrated to give 10f (150 mg).

E. 3-Chloro-6-trifluoromethyl-7-fluoro-benzo[b]thiophene-2-carboxylicacid, 10g

Compound 10g was prepared from 10e following the procedure described inabove step D.

Following the procedure described above for Example 10, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 6661-(1-{[3-Chloro-5-fluoro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 533 9001-(1-{[3-Chloro-5-fluoro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 533 6701-(1-{[3-Chloro-7-fluoro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 533 6501-(1-{[3-Chloro-7-fluoro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 533

Example 10b

F. 3-Chloro-5-trifluoromethyl-6-fluoro-benzo[b]thiophene-2-carboxylicacid, 10h and3-chloro-6-fluoro-7-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid,10i

Compounds 10h and 10i were prepared according to Example 10a, using4-fluoro-3-(trifluoromethyl)-cinnamic acid in place of 10c, and wereobtained as a ˜2:1 mixture.

G. 3-Chloro-5-trifluoromethyl-6-fluoro-benzo[b]thiophene-2-carbonylchloride, 10j and3-chloro-6-fluoro-7-trifluoromethyl-benzo[b]thiophene-2-carbonylchloride, 10k

Compounds 10j and 10k were prepared according to Example 10a from 10hand 10i, and were obtained as a ˜2:1 mixture.

H.1-(1-{[3-Chloro-6-fluoro-5-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 901, and1-(1-{[3-chloro-6-fluoro-7-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 902

Cpd 901 and Cpd 902 were prepared according to Example 10 from 5e bisHCl salt (0.31 mmol, 150 mg), the mixture of 10j and 10k (0.24 mmol, 76mg), and Et₃N (1.44 mol, 0.2 mL) in 7 mL of CH₂Cl₂. Workup andpurification by flash column chromatography (silica gel, 2% MeOH/CH₂Cl₂)gave 50 mg (39%) of Cpd 901 followed by 18 mg (14%) of Cpd 902. Cpd 901:MS m/z (M+H⁺) 533. Cpd 902: MS m/z (M+H⁺) 533.

Following the procedure described above for Example 10b, andsubstituting the appropriate reagents, starting materials, andpurification methods known to those skilled in the art, the followingcompounds of the present invention were prepared:

Cpd Cpd Name and Data 6591-(1-{[3-Chloro-6-fluoro-5-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 533 6971-(1-{[3-Chloro-6-fluoro-7-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 533

Example 11

A.1-{4-[1-(6-Bromo-3-chloro-benzo[b]thiophene-2-carbonyl)-azetidin-3-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone,11b

To a solution of compound 1g (0.19 g, 0.61 mmol) and Et₃N (0.51 mL, 3.67mmol) in CH₂Cl₂ (4 mL) at 0° C. was added a solution of compound 11a(prepared in an analogous manner to that of compound 10b of Example 10)(0.69 mmol) in CH₂Cl₂ (2 mL). The reaction mixture was slowly warmed upto room temperature over 18 h. The reaction mixture was diluted withCH₂Cl₂ and washed with aq. NaHCO₃. The organic layer was dried overNa₂SO₄ and concentrated. Purification by flash column chromatography(silica gel, 3% MeOH/CH₂Cl₂) gave compound 11b (0.3 g).

B.(6-Bromo-3-chloro-benzo[b]thiophen-2-yl)-(3-piperazin-1-yl-azetidin-1-yl)-methanone,11c

A solution of compound 11b (0.3 g, 0.59 mmol) in Et₃N (1 mL) and MeOH (9mL) was stirred at room temperature for 3 days. It was then concentratedto give compound 11c, which was used in the next reaction withoutfurther purification.

C.1-{1-[(6-Bromo-3-chloro-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 326

To a mixture of compound 11c (0.2 mmol), compound 5c (31 mg, 0.24 mmol),and Et₃N (0.08 mL, 0.58 mmol) in CH₂Cl₂ (3 mL) at room temperature wasadded HATU (91 mg, 0.24 mmol). The reaction mixture was stirred at roomtemperature for 18 h. It was diluted with diethyl ether, washed with aq.NaHCO₃ and aq. NaCl, dried over Na₂SO₄, filtered, and concentrated.Purification by flash column chromatography (silica gel, 3% MeOH/CH₂Cl₂)gave compound 326 (57 mg). ¹H NMR (400 MHz, CD₃OD): δ 7.98 (s, 1H), 7.88(d, J=3 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.55(d, J=3 Hz, 1H), 4.53 (bs, 1H), 4.44 (bs, 1H), 4.30 (bs, 2H), 4.21 (bs,1H), 4.13 (bs, 1H), 3.89 (bs, 1H), 3.84 (bs, 1H), 3.31 (m, 1H),2.60-2.40 (m, 4H). MS m/z (M+H⁺) 525/527/529.

Following the procedure described above for Example 11 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 3271-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (400 MHz,CD₃OD): δ 8.05 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 3 Hz, 1H), 7.85 (s,1H), 7.72 (d, J = 7.4 Hz, 1H), 7.55 (d, J = 3 Hz, 1H), 7.51 (t, J = 7.8Hz, 1H), 4.60 (m, 2H), 4.45 (m, 2H), 4.31 (m, 1H), 4.17 (m, 1H),3.95-3.80 (m, 2H), 3.35 (m, 1H), 2.56 (bs, 4H). MS m/z (M + H⁺) 481 3281-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[7-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 481329 1-(Phenylcarbonyl)-4-(1-{[7-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (400 MHz,CD₃OD): δ 8.02 (d, J = 8.2 Hz, 1H), 7.80 (s, 1H), 7.73 (d, J = 7.4 Hz,1H), 7.51 (t, J = 8.2 Hz, 1H), 7.42 (m, 5H), 4.60 (m, 1H), 4.43 (m, 1H),4.28 (m, 1H), 4.12 (m, 1H), 3.94 (bs, 1H), 3.76 (bs, 1H), 3.51 (bs, 2H),3.33 (m, 1H), 2.60-2.30 (m, 4H). MS m/z (M + H⁺) 474 3301-(Phenylcarbonyl)-4-(1-{[4-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (400 MHz,CD₃OD): δ 8.05 (d, J = 8 Hz, 1H), 7.84 (s, 1S), 7.71 (d, J = 8 Hz, 1H),7.50 (t, J = 8 Hz, 1H), 7.42 (m, 5H), 4.59 (m, 1H), 4.42 (m, 1H), 4.29(m, 1H), 4.13 (m, 1H), 3.92 (bs, 1H), 3.79 (bs, 1H), 3.51 (bs, 1H), 3.34(m, 1H), 2.60- 2.30 (m, 4H). MS m/z (M + H⁺) 474 3311-{1-[(6-Bromo-3-chloro-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺)518/520/522 3321-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[7-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (400 MHz,CD₃OD): δ 8.80 (s, 1H), 8.04 (s, 1H), 8.02 (d, J = 8 Hz, 1H), 7.81 (s,1H), 7.73 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 4.60 (m, 1H),4.45 (m, 1H), 4.30 (m, 1H), 4.15 (m, 1H), 4.02 (bs, 1H), 3.95 (m, 2H),3.82 (bs, 1H), 3.35 (m, 1H), 2.60-2.40 (m, 4H). MS m/z (M + H⁺) 481 3331-{1-[(6-Bromo-3-chloro-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹HNMR (400 MHz, CD₃OD): δ 8.80 (s, 1H), 8.02 (s, 1H), 7.97 (s, 1H), 7.74(m, 1H), 7.60 (m, 1H), 4.30 (m, 2H), 4.21 (bs, 1H), 4.12 (bs, 1H), 4.00(bs, 1H), 3.92 (m, 2H), 3.81 (bs, 1H), 3.31 (m, 1H), 2.50-2.30 (m, 4H).MS m/z (M + H⁺) 525/527/529 3341-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[4-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (400 MHz,CD₃OD): δ 8.80 (s, 1H), 8.05 (d, J = 8 Hz, 1H), 8.04 (s, 1H), 7.85 (m,1H), 7.72 (d, J = 8 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 4.60 (m, 1H),4.44 (m, 1H), 4.30 (m, 1H), 4.16 (m, 1H), 4.10-3.80 (m, 4H), 3.36 (m,1H), 2.60-2.40 (m, 4H). MS m/z (M + H⁺) 481 3351-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹HNMR (400 MHz, CD₃OD): δ 8.80 (d, J = 2 Hz, 1H), 8.13 (t, J = 0.8 Hz,1H), 8.03 (d, J = 2 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.73 (dd, J = 1.2Hz, 8.6 Hz, 1H), 4.31 (m, 2H), 4.21 (m, 1H), 4.15 (m, 1H), 4.01 (m, 1H),3.93 (m, 2H), 3.81 (m, 1H), 3.33 (m, 1J), 2.55-2.40 (m, 4H). MS m/z (M +H⁺) 515 336 1-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺)508 337 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 481504 1-(1-{[3-Methyl-5-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺)488 543 1-{1-[(3-Chloro-6-fluoro-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺)458 516 1-{1-[(6-Fluoro-3-methyl-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺)438 908 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[5-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 481897 1-(1-{[3-Methyl-5-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 495 8981-(1-{[3-Methyl-5-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 495 929 1-{1-[(3-Chloro-6-fluoro-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 465 930 1-{1-[(3-Chloro-6-fluoro-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 465 810 1-{1-[(3-Chloro-6-fluoro-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(pyridin-2-ylcarbonyl)piperazine MS m/z(M + H⁺) 459 742 1-{1-[(6-Fluoro-3-methyl-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 445 684 1-{1-[(6-Fluoro-3-methyl-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 445

Example 12

1-{1-[(5-Phenylnaphthalen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 338

A mixture of compound 313 (48 mg, 0.1 mmol), compound 12a (24 mg, 0.2mmol), K₂CO₃ (27 mg, 0.2 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (4 mg, 0.005 mmol)in EtOH (1 mL) and H₂O (0.2 mL) was heated in a microwave reactor at130° C. for 30 min. The reaction mixture was cooled to room temperature,diluted with CH₂Cl₂, and washed with H₂O. The organic layer was driedover Na₂SO₄ and concentrated. Purification by flash columnchromatography (silica gel, 3% MeOH/CH₂Cl₂) gave compound 338 (28 mg).¹H NMR (400 MHz, CD₃OD): δ 8.20 (d, J=1.6 Hz, 1H), 7.93 (t, J=9.6 Hz,2H), 7.88 (d, J=3 Hz, 1H), 7.66-7.43 (m, 9H), 4.52 (bs, 1H), 4.50-4.20(m, 4H), 4.16 (m, 1H), 3.88 (bs, 1H), 3.83 (bs, 1H), 3.28 (m, 1H),2.60-2.40 (m, 4H). MS m/z (M+H⁺) 483.

Following the procedure described above for Example 12 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 3391-(Phenylcarbonyl)-4-{1-[(6-phenylnaphthalen-2-yl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 476 3407-Phenyl-3-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M + H⁺) 477 3411-(Phenylcarbonyl)-4-[1-({6-[4-(trifluoromethyl)phenyl]-1-benzothiophen-2-yl}carbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 550342 1-{1-[(6-Phenyl-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine ¹H NMR (400 MHz, CD₃OD): δ 8.05 (s,1H), 7.88 (d, J = 8.6 Hz, 1H), 7.70 (s, 1H), 7.66-7.62 (m, 3H),7.49-7.36 (m, 8H), 4.58 (m, 1H), 4.42 (m, 1H), 4.28 (m, 1H), 4.11 (m,1H), 3.92 (bs, 1H), 3.76 (bs, 1H), 3.49 (bs, 2H), 3.31 (m, 1H),2.60-2.25 (m, 4H). MS m/z (M + H⁺) 482

Example 13

1-{1-[(3-Chloro-6-phenyl-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 343

The title compound was prepared in an analogous manner to that ofcompound 338 of Example 12, using 1 equivalent of compound 12a, andsubstituting compound 326 for compound 313. The reaction was heated in amicrowave reactor at 120° C. for 20 min ¹H NMR (400 MHz, CD₃OD): δ 8.01(d, J=1.2 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.88 (d, J=3 Hz, 1H), 7.74(d, J=8.6 Hz, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.55 (d, J=3 Hz, 1H), 7.49(m, 2H), 7.41 (m, 1H), 4.54 (bs, 1H), 4.46 (bs, 1H), 4.33 (m, 2H), 4.25(m, 1H), 4.14 (m, 1H), 3.89 (bs, 1H), 3.84 (bs, 1H), 3.32 (m, 1H), 2.50(m, 4H). MS m/z (M+H⁺) 523.

Following the procedure described above for Example 13 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 344 1-{1-[(3-Chloro-6-phenyl-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺)516 (M + H⁺). 345 1-{1-[(3-Chloro-6-phenyl-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 523 5911-(Phenylcarbonyl)-4-(1-{[3-phenyl-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 550515 1-(1-{[3-Cyclopropyl-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺)514 511 1-(1-{[3-(2-Methylprop-1-en-1-yl)-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazineMS m/z (M + H⁺) 528

Example 14

1-(Phenylcarbonyl)-4-{1-[(5-phenylthiophen-2-yl)carbonyl]azetidin-3-yl}piperazine,Cpd 346

A mixture of compound 322 (40 mg), compound 12a (16 mg),Pd(dppf)Cl₂.CH₂Cl₂ (8 mg), and Na₂CO₃ (19 mg), in a dioxane (0.8mL)/water (0.2 mL) mixture, was placed in a capped vial and heated at80° C. for 4 h. The reaction mixture was then diluted with EtOAc andwater. The organic layer was concentrated under reduced pressure andpurified by flash column chromatography (silica gel, 5% MeOH/EtOAc) togive compound 346 (17 mg). MS m/z (M+H⁺) 432.6.

Following the procedure described above for Example 14 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 347 1-(Phenylcarbonyl)-4-[1-({5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}carbonyl)azetidin-3- yl]piperazineMS m/z (M + H⁺) 500.0 924 1-Acetyl-6-phenyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline MS m/z (M + H⁺) 530.0 9171-Acetyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-6-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinoline MS m/z (M + H⁺) 598.0 9191-Acetyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-6-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinoline MS m/z (M + H⁺) 598.0 9201-Acetyl-6-(5-chlorothiophen-2-yl)-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline MS m/z (M + H⁺) 570.1 11571-(1-{[4-(4-Fluorophenyl)thiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 457.0 11601-(1-{[4-(3-Fluorophenyl)thiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 457.0 13211-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[3-(trifluoromethyl)phenyl]thiophen-2-yl}carbonyl)azetidin-3- yl]piperazineMS m/z (M + H⁺) 507.0 6051-{1-[(5-Phenyl-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 466 6007-(3-Fluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 483 13421-{1-[(5-Phenyl-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 473 13431-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({5-[3-(trifluoromethyl)phenyl]-1-benzofuran-2-yl}carbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 541 10591-(1-{[4-(3-Fluorophenyl)-5-methylthiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 471 13511-[1-({5-Methyl-4-[3-(trifluoromethyl)phenyl]thiophen-2-yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 521 10667-(3-Fluorophenyl)-1-methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 504 1101 7-(4-Fluorophenyl)-1-methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 504 1060 1-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-7-[3-(trifluoromethyl)phenyl]-1H- indole MSm/z (M + H⁺) 554 13521-[1-({4-Methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 521 1353 1-(1-{[5-(4-Fluorophenyl)-4-methylthiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine 10651-(1-{[5-(3-Fluorophenyl)-4-methylthiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 471 13541-[1-({4-Methyl-5-[3-(trifluoromethyl)phenyl]thiophen-2-yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 521 1183 7-(3-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 490 1096 1-(1-{[4-(4-Fluorophenyl)-5-methylthiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 471

Example 14a

Following the procedure described above for Example 14, substituting Cpd682 of Example 5 for Cpd 322 and substituting the appropriate reagents,starting materials, and purification methods known to those skilled inthe art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 10755-(4-Fluorophenyl)-3-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole ¹H NMR (400MHz, CDCl₃): δ 7.93 (ar, 1H); 7.82 (ar, 1H); 7.76 (ar, 1H); 7.64 (m,2H); 7.46 (m, 2H); 7.15 (m, 2H); 4.47-4.0 (bm, 6H); 3.82 (b, 2H); 2.5(s, 3H) MS m/z (M + H⁺) 504.1 11495-(2-Fluoropyridin-3-yl)-3-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole ¹H NMR (400MHz, CDCl₃): δ 8.09-7.97 9m, 2H); 7.88 (ar, 1H); 7.82-7.72 (m, 2H); 7.42(ar, 2H); 7.31 (m, 1H); 7.62 (bm, 1H); 4.48 (bm, 1H); 4.35 (bm, 2H);3.96 (bm, 2H); 3.14 (m, 4H); 2.44 (s, 3H) MS m/z (M + H⁺) 505.2 11755-(5-Methoxypyridin-3-yl)-3-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 517.2 1205 3-Methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)- 1H-indoleMS m/z (M + H⁺) 490.2

Example 14b

Following the procedure described above for Example 14, substituting Cpd792 of Example 5 for Cpd 322 and substituting the appropriate reagents,starting materials, and purification methods known to those skilled inthe art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1204 6-(4-Fluorophenyl)-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 491.1 1241 6-(1-Methyl-1H-pyrazol-5-yl)-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 477.3 1244 6-(2-Fluoropyridin-3-yl)-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 491.2 1211 6-(3,5-Dimethylisoxazol-4-yl)-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 491.1 1196 6-(5-Methoxypyridin-3-yl)-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 503.1

Example 14c

Following the procedure described above for Example 14, substituting Cpd864 of Example 5 for Cpd 322 and substituting the appropriate reagents,starting materials, and purification methods known to those skilled inthe art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1213 5-(4-Fluorophenyl)-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)furo[2,3- b]pyridine MSm/z (M + H⁺) 492.1 12095-Phenyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)furo[2,3-b]pyridine MS m/z (M + H⁺) 474.1

Example 14d

Following the procedure described above for Example 14, substituting Cpd315 of Example 5 for Cpd 322 and substituting the appropriate reagents,starting materials, and purification methods known to those skilled inthe art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 14435-Fluoro-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 415.2 14765-(2-Fluoropyridin-3-yl)-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 492.1 13032-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-5-[4-(trifluoromethoxy)phenyl]-1H- benzimidazole MS m/z(M + H⁺) 494.97 1294 5-(4-Fluorophenyl)-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole; MSm/z (M + H⁺) 491.1

Example 15

1-(Phenylcarbonyl)-4-(1-{[5-(phenylethynyl)thiophen-2-yl]carbonyl}azetidin-3-yl)piperazine,Cpd 348

To a solution of compound 322 (100 mg), compound 15a (0.46 mmol, 0.05mL), CuI (4.4 mg), and Pd(PPh₃)₂Cl₂ (16 mg) in THF (1 mL) was added TEA(0.25 mL) and the mixture was heated at 40° C. for 1 h. The reaction wasdiluted with EtOAc and water. The organics were concentrated andpurified by flash column chromatography (silica gel, 5% MeOH/EtOAc) toyield compound 348 (75 mg). MS m/z (M+H⁺) 456.6.

Example 16

1-(Phenylcarbonyl)-4-(1-{[5-(2-phenylethyl)thiophen-2-yl]carbonyl}azetidin-3-yl)piperazine,Cpd 349

To a solution of compound 348 (30 mg) in EtOH (20 mL) was added 10% Pd/C(10 mg) and the mixture was subjected to hydrogenation (45 psi H₂) for1.5 h. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure to give compound 349 (30 mg). MS m/z(M+H⁺) 460.6.

Example 17

A.6-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline,17a

To a solution of compound 319 (500 mg) in CH₂Cl₂ (6 mL) was added TFA (4mL) at room temperature. The mixture was stirred for 1.5 h and was thenconcentrated under reduced pressure. The residue was diluted with CH₂Cl₂and made basic with aqueous 2N NaOH solution. The organic layer waswashed with water and brine, dried over anhydrous K₂CO₃, filtered, andconcentrated to give compound 17a, which was used without furtherpurification.

B.2-(Cyclohexylcarbonyl)-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline,Cpd 350

A mixture of compound 17a (31 mg, 0.03 mL), HATU (100 mg), and TEA (0.11mL) in DCM (1 mL) was stirred at room temperature for 5 h. The reactionwas diluted with DCM and water. The organics were concentrated andpurified by flash column chromatography (silica gel, 8% MeOH/EtOAc) togive compound 350 (65 mg). ¹H NMR (CDCl₃): δ 7.47-7.39 (m, 7H), 7.17 (d,J=0.02, 1H), 4.74 (s, 1.2H), 4.48 (s, 0.8H), 4.25 (m, 2H), 4.10 (m, 2H),3.92-3.71 (m, 4H), 3.43 (m, 2H), 3.19 (m, 1H), 2.93 (m, 1.2H), 2.86 (m,0.8H), 2.55 (m, 1H), 2.42-2.24 (m, 4H), 1.83-1.57 (m, 8H), 1.26 (m, 2H).MS m/z (M+H⁺) 515.7.

Following the procedure described above for Example 17 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 3512-(3,3-Dimethylbutanoyl)-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M +H⁺) 503.7 3522-(3,3-Dimethylbutanoyl)-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M +H⁺) 509.6 353 2-[(4,4-Difluorocyclohexyl)carbonyl]-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 463.6 3546-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-{[4-(trifluoromethyl)cyclohexyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 583.7 5461-(1-{[4-(1-Acetylpiperidin-4-yl)phenyl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 475.2 14861-[1-({2-[(3S)-1-Acetylpyrrolidin-3-yl]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z(M + H⁺) 461.2 1437 2-(Phenylcarbonyl)-8-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 516.2

Example 17a

D.6-{3-[4-(Thiazole-2-carbonyl)-piperazin-1-yl]-azetidine-1-carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester, 17c

To a solution of compound 5e (651 mg, 2 mmol),3,4-dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester 17b(555 mg, 2 mmol), and EDC (466 mg, 3 mmol) in CH₂Cl₂ (20 mL) was addedEt₃N (0.84 mL, 6 mmol). The reaction mixture was stirred at roomtemperature overnight. The mixture was extracted with CH₂Cl₂, and H₂Oafter acidifying the water layer to pH˜6 with 1N aqueous HCl. Theorganic solution was dried over Na₂SO₄ and concentrated. Purification ofthe residue by flash column chromatography (silica gel, 2% MeOH/EtOAc)gave 17c (826 mg). MS m/z (M+H⁺) 512.1.

Following the procedure described above for Example 17a, andsubstituting the appropriate reagents, starting materials, andpurification methods known to those skilled in the art, the followingintermediate compounds were prepared:

Following the procedure described above for Example 17a, andsubstituting the appropriate reagents, starting materials, andpurification methods known to those skilled in the art, the followingcompounds of the present invention were prepared:

Cpd Cpd Name and Data 538 tert-Butyl4-[3-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]piperidine-1-carboxylate MS m/z (M +H⁺) 533.4 903 tert-Butyl4-[4-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]piperidine-1- carboxylate MS m/z (M +H⁺) 540.1 861 tert-Butyl 8-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3,4-dihydroisoquinoline- 2(1H)-carboxylate MSm/z (M + H⁺) 512.2

Example 17b

E.6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline,Cpd 916

To a solution of compound 17c (826 mg, 1.61 mmol) in CH₂Cl₂ (5 mL) wasadded trifluoroacetic acid (1 mL) at room temperature. The mixture wasstirred at room temperature for 18 h. The mixture was extracted withCH₂Cl₂, and H₂O after basifying the water layer to pH˜8 with 1N aqueousNaOH. The organic solution was dried over Na₂SO₄ and concentrated.Purification of the residue by flash column chromatography (silica gel,2% MeOH/EtOAc) gave Cpd 916 (675 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.88(d, J=3.3 Hz, 1H), 7.55 (d, J=3.3 Hz, 1H), 7.41 (s, 1H), 7.37 (d, J=8.03Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 4.54 (br. s., 1H), 4.44 (br. s., 1H),4.01-4.35 (m, 6H), 3.75-3.95 (m, 2H), 3.12-3.31 (m, 2H), 2.85 (t, J=5.8Hz, 1H), 2.49 (br. s., 4H). MS m/z (M+H⁺) 412.0.

Following the procedure described above for Example 17b, andsubstituting the appropriate reagents, starting materials, andpurification methods known to those skilled in the art, the followingintermediate compounds were prepared:

Example 18

2-Benzyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline,Cpd 355

To a suspension of compound 17a (100 mg) and K₂CO₃ (69 mg) in MeCN wasadded compound 18a (0.0353 mL) and the mixture was stirred at roomtemperature for 30 min. The reaction was concentrated and the residuewas diluted with EtOAc and water. The organics were concentrated andpurified by flash column chromatography (silica gel, 8% MeOH/EtOAc) toafford compound 355 (85 mg). MS m/z (M+H⁺) 495.6.

Example 19

N-tert-Butyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide,Cpd 356

To a solution of compound 17a (75 mg) in DCM (1 mL) was dropwise addedcompound 19a (0.026 mL) at 0° C. After 30 min, the reaction mixture wasquenched with DCM and water at 0° C. The organics were concentrated andpurified by flash column chromatography (silica gel, 5% MeOH/EtOAc) togive compound 356 (60 mg). MS m/z (M+H⁺) 504.7.

Example 20

A.6-({3-[4-(Trifluoroacetyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline,20b

To a solution of compound 1g (308 mg, 1 mmol), compound 20a (177 mg, 1mmol), and Et₃N (0.42 mL, 3 mmol) in CH₂Cl₂ (10 mL) was added HATU (570mg, 1.5 mmol). The reaction mixture was stiffed at room temperature for18 h. The resultant mixture was diluted with CH₂Cl₂ and washed with aq.NaHCO₃. The organic phase was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. Purification by flash columnchromatography (silica gel, 2% MeOH/EtOAc+0.5% Et₃N) gave compound 20b(279 mg). LC/MS m/z (M+H⁺) 397.0.

B.6-([3-piperazin-1-yl]-azetidin-1-yl)carbonyl-1,2,3,4-tetrahydroquinoline,20c

To a solution of compound 20b (529 mg, 1.33 mmol) in MeOH (10 mL) wasadded K₂CO₃ (368 mg, 2.66 mmol). The reaction mixture was stiffed atroom temperature for 30 min. The resultant mixture was filtered,concentrated under reduced pressure, and the resultant residue waspartitioned between CH₂Cl₂ and H₂O. The organic phase was dried overNa₂SO₄, filtered, and concentrated under reduced pressure to givecompound 20c (370 mg). LC/MS m/z (M+H⁺) 301.0.

C.6-(3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]-azetidin-1-yl)carbonyl-1,2,3,4-tetrahydroquinoline,Cpd 357

To a solution of compound 20c (370 mg, 1.23 mmol), compound 5c (160 mg,1.24 mmol), and Et₃N (0.51 mL, 3.69 mmol) in CH₂Cl₂ (10 mL) was addedHATU (703 mg, 1.85 mmol). The reaction mixture was stirred at roomtemperature for 18 h. The resultant mixture was diluted with CH₂Cl₂ andwashed with aq. NaHCO₃. The organic phase was dried over Na₂SO₄,filtered, and concentrated under reduced pressure. Purification of theresidue by flash column chromatography (silica gel, 2% MeOH/EtOAc+0.5%Et₃N) gave compound 357 (483 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d,J=3.0 Hz, 1H), 7.53-7.58 (m, 1H), 7.33 (s, 1H), 7.24-7.30 (m, 1H), 6.39(d, J=8.1 Hz, 1H), 3.97-4.66 (m, 6H), 3.86 (d, J=18.4 Hz, 2H), 3.35 (t,J=5.4 Hz, 2H), 3.16-3.26 (m, 1H), 2.77 (t, J=6.2 Hz, 2H), 2.39-2.59 (m,4H), 1.94 (dt, J=11.8, 6.1 Hz, 2H); LC/MS m/z (M+H⁺) 412.0.

Example 21

6-(3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]-azetidin-1-yl)carbonyl1-[3-(trifluoromethyl)phenyl]carbonyl-1,2,3,4-tetrahydroquinoline, Cpd358

To a solution of compound 357 (30 mg, 0.073 mmol) in CH₂Cl₂ (1 mL), at0° C., was added compound 1f (0.013 mL, 0.088 mmol), then Et₃N (0.03 mL,0.22 mmol). The reaction mixture was stirred at 0° C. for 2 h. Theresultant mixture was partitioned between CH₂Cl₂ and H₂O. The organicphase was dried over Na₂SO₄, filtered, and concentrated under reducedpressure. Purification of the residue by flash column chromatography(silica gel, 2% MeOH/EtOAc+0.5% Et₃N) gave compound 358 (42 mg). ¹H NMR(400 MHz, CDCl₃): δ 7.88 (d, J=3.3 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.61(s, 1H), 7.52-7.59 (m, 3H), 7.41-7.49 (m, 1H), 7.12 (dd, J=8.3, 1.8 Hz,1H), 6.73 (d, J=7.8 Hz, 1H), 4.35-4.59 (m, 2H), 4.18-4.26 (m, 2H),4.01-4.16 (m, 2H), 3.75-3.95 (m, 4H), 3.17-3.26 (m, 1H), 2.90 (t, J=6.6Hz, 2H), 2.37-2.57 (m, 4H), 2.02-2.12 (m, 2H); LC/MS m/z (M+H⁺) 584.0.

Following the procedure described above for Example 21 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 3591-(Cyclopropylcarbonyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H),7.55 (d, J = 3.3 Hz, 1H), 7.50 (s, 1H), 7.43-7.47 (m, 2H), 4.05-4.62 (m,6H), 3.75-3.97 (m, 4H), 3.21-3.31 (m, 1H), 2.78 (t, J = 6.6 Hz, 2H),2.38-2.59 (m, 4H), 1.90-2.03 (m, 3H), 1.13-1.21 (m, 2H), 0.80-0.86 (m,2H); LC/MS m/z (M + H⁺) 480.0. 3601-(Cyclohexylcarbonyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J = 3.0 Hz, 1H),7.55 (d, J = 3.3 Hz, 1H), 7.50 (s, 1H), 7.44 (dd, J = 8.2, 1.6 Hz, 1H),7.28-7.33 (m, 1H), 4.04-4.62 (m, 6H), 3.73-3.96 (m, 4H), 3.21- 3.30 (m,1H), 2.72-2.82 (m, 3H), 2.40-2.59 (m, 4H), 1.98 (quin, J = 6.6 Hz, 2H),1.71-1.83 (m, 4H), 1.49-1.70 (m, 2H), 1.10- 1.36 (m, 4H); LC/MS m/z (M +H⁺) 522.2. 361 1-(Methylsulfonyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J = 3.0 Hz, 1H),7.74 (d, J = 8.6 Hz, 1H), 7.55 (d, J = 3.3 Hz, 1H), 7.51 (d, J = 1.8 Hz,1H), 7.40 (dd, J = 8.6, 2.3 Hz, 1H), 4.03-4.61 (m, 6H), 3.78-3.96 (m,4H), 3.21-3.29 (m, 1H), 2.95 (s, 3H), 2.89 (t, J = 6.6 Hz, 2H),2.40-2.59 (m, 4H), 1.97-2.08 (m, 2H); LC/MS m/z (M + H⁺) 490.0. 3621-(Methylsulfonyl)-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 8.79 (d, J = 2.0 Hz, 1H),8.02 (d, J = 2.3 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.49 (s, 1H), 7.39(dd, J = 8.7, 2.1 Hz, 1H), 3.72-4.37 (m, 10H), 3.19-3.30 (m, 1H), 2.94(s, 3H), 2.87 (t, J = 6.6 Hz, 2H), 2.33-2.56 (m, 4H), 1.96-2.04 (m, 2H);LC/MS m/z (M + H⁺) 490.0. 3631-(Methylsulfonyl)-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline ¹H NMR (400 MHz,CDCl₃): δ 7.73 (d, J = 8.6 Hz, 1H), 7.49 (s, 1H), 7.35-7.44 (m, 6H),4.00-4.36 (m, 4H), 3.64-3.97 (m, 4H), 3.48 (br. s., 2H), 3.18-3.27 (m,1H), 2.91-2.97 (m, 3H), 2.87 (t, J = 6.6 Hz, 2H), 2.19-2.56 (m, 4H),1.97-2.04 (m, 2H); LC/MS m/z (M + H⁺) 483.0. 3641-(Cyclobutylcarbonyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J = 3.0 Hz, 1H),7.55 (d, J = 3.3 Hz, 1H), 7.48 (s, 1H), 7.39-7.44 (m, 1H), 7.24-7.28 (m,1H), 4.01-4.63 (m, 6H), 3.78-3.97 (m, 2H), 3.67-3.76 (m, 2H), 3.48(quin, J = 8.4 Hz, 1H), 3.20-3.30 (m, 1H), 2.76 (t, J = 6.3 Hz, 2H),2.34-2.60 (m, 6H), 2.08 (m, 2H), 1.83-2.02 (m, 4H); LC/MS m/z (M + H⁺)494.0. 365 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(4-trifluoromethylbenzoyl)-1,2,3,4- tetrahydroquinoline¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H), 7.52- 7.61 (m, 4H),7.49 (d, J = 8.1 Hz, 2H), 7.12-7.18 (m, 1H), 6.75- 6.85 (m, 1H),4.00-4.60 (m, 6H), 3.76-3.95 (m, 4H), 3.18-3.27 (m, 1H), 2.90 (t, J =6.6 Hz, 2H), 2.37-2.57 (m, 4H), 2.02-2.12 (m, 2H); LC/MS m/z (M + H⁺)584.0. 729 2-[(4,4-Difluorocyclohexyl)carbonyl]-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 558.0 6796-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-{[3-(trifluoromethyl)phenyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J = 3.3 Hz,1H), 7.70- 7.79 (m, 2H), 7.63-7.68 (m, 1H), 7.57-7.62 (m, 1H), 7.55 (d,J = 3.3 Hz, 1H), 7.50 (s, 1H), 7.45 (br. s., 1H), 7.26 (s, 1H), 4.94(br. s., 1H), 4.48-4.66 (m, 2H), 4.44 (br. s., 1H), 3.97-4.36 (m, 5H),3.75-3.96 (m, 2H), 3.65 (br. s., 1H), 3.19-3.33 (m, 1H), 2.85-3.12 (m,2H), 2.37-2.62 (m, 4H) MS m/z (M + H⁺) 584.0 9076-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-{[4-(trifluoromethyl)phenyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J = 3.3 Hz,1H), 7.72 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 7.6 Hz, 2H), 7.55 (d, J =3.3 Hz, 1H), 7.38-7.52 (m, 2H), 7.21-7.27 (m, 1H), 4.94 (br. s., 1H),4.48-4.65 (m, 2H), 4.43 (br. s., 1H), 3.95-4.36 (m, 5H), 3.73-3.95 (m,2H), 3.62 (br. s., 1H), 3.19-3.32 (m, 1H), 2.85- 3.10 (m, 2H), 2.38-2.59(m, 4H) MS m/z (M + H⁺) 584.0 6856-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-{[4-(trifluoromethyl)cyclohexyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 590.0 7362-(Phenylcarbonyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 516.0 6656-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-(thiophen-2-ylcarbonyl)-1,2,3,4- tetrahydroisoquinolineMS m/z (M + H⁺) 522.0 6902-(1H-Pyrrol-2-ylcarbonyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 505

Example 22

1-(Phenylsulfonyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline,Cpd 366

To a solution of compound 357 (60 mg, 0.015 mmol) in pyridine (1 mL) wasadded compound 22a (0.023 mL, 0.017 mmol). The reaction mixture wasstiffed at room temperature for 2 h. The resultant mixture wasconcentrated under reduced pressure and purified by flash columnchromatography (silica gel, 2% MeOH/EtOAc+0.5% Et₃N) to give compound366 (66 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J=3.3 Hz, 1H), 7.84 (d,J=8.3 Hz, 1H), 7.61-7.67 (m, 2H), 7.52-7.59 (m, 2H), 7.36-7.47 (m, 4H),4.03-4.61 (m, 6H), 3.78-3.93 (m, 4H), 3.20-3.30 (m, 1H), 2.41-2.58 (m,6H), 1.63-1.71 (m, 2H); LC/MS m/z (M+H⁺) 552.0.

Following the procedure described above for Example 22 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 3676-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1,2,3,4-tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.87-7.91 (m, 2H),7.78-7.86 (m, 3H), 7.57-7.63 (m, 1H), 7.54-7.57 (m, 1H), 7.39-7.45 (m,2H), 4.07-4.61 (m, 6H), 3.77-3.95 (m, 4H), 3.20-3.30 (m, 1H), 2.41-2.59(m, 6H), 1.70 (quin, J = 6.3 Hz, 2H); LC/MS m/z (M + H⁺) 620.0. 3681-[(3-Fluorophenyl)sulfonyl]-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J = 3.0 Hz, 1H),7.81 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 3.0 Hz, 1H), 7.38-7.47 (m, 4H),7.32-7.37 (m, 1H), 7.22-7.29 (m, 1H), 4.02-4.61 (m, 6H), 3.77- 3.96 (m,4H), 3.20-3.30 (m, 1H), 2.40-2.60 (m, 6H), 1.65-1.77 (m, 2H); LC/MS m/z(M + H⁺) 570.0. 3696-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[(4-trifluoromethylphenyl)sulfonyl]-1,2,3,4-tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H),7.80- 7.85 (m, 1H), 7.73-7.79 (m, 2H), 7.68-7.73 (m, 2H), 7.55 (d, J =3.3 Hz, 1H), 7.39-7.44 (m, 2H), 4.02-4.61 (m, 6H), 3.77-3.95 (m, 4H),3.21-3.29 (m, 1H), 2.39-2.59 (m, 6H), 1.65-1.73 (m, 2H); LC/MS m/z (M +H⁺) 620.0 927 2-(Phenylsulfonyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 552.0 9286-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 619.8 9062-(Cyclohexylsulfonyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 558.0

Example 23

1-Benzyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline,Cpd 370

To a solution of compound 357 (30 mg, 0.0073 mmol) in CH₃CN (1 mL) wasadded compound 18a (0.01 mL, 0.0088 mmol), followed by the addition ofK₂CO₃ (20 mg, 0.015 mmol). The reaction mixture was stirred at roomtemperature for 18 h. The resultant mixture was partitioned betweenCH₂Cl₂ and H₂O. The organic solution was dried over Na₂SO₄, filtered,and concentrated under reduced pressure. Purification of the residue byflash column chromatography (silica gel, 1% MeOH/EtOAc+0.5% Et₃N) gavecompound 370 (14 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J=3.3 Hz, 1H),7.54 (d, J=3.0 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.30-7.36 (m, 2H),7.19-7.30 (m, 4H), 6.44 (d, J=8.6 Hz, 1H), 4.54 (s, 2H), 3.97-4.52 (m,6H), 3.77-3.96 (m, 2H), 3.40-3.47 (m, 2H), 3.15-3.24 (m, 1H), 2.83 (t,J=6.2 Hz, 2H), 2.38-2.59 (m, 4H), 1.98-2.05 (m, 2H); LC/MS m/z (M+H⁺)502.2.

Following the procedure described above for Example 23 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 3716-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(4-trifluoromethylbenzyl)-1,2,3,4- tetrahydroquinoline ¹HNMR (400 MHz, CDCl₃): δ 7.88 (d, J = 3.0 Hz, 1H), 7.59 (d, J = 8.3 Hz,2H), 7.54 (d, J = 3.0 Hz, 1H), 7.39 (s, 1H), 7.34 (d, J = 8.1 Hz, 2H),7.23-7.29 (m, 1H), 6.35 (d, J = 8.6 Hz, 1H), 4.58 (s, 2H), 3.97-4.54 (m,6H), 3.74-3.97 (m, 2H), 3.39-3.49 (m, 2H), 3.15-3.26 (m, 1H), 2.85 (t, J= 6.1 Hz, 2H), 2.38-2.59 (m, 4H), 1.99-2.10 (m, 2H); LC/MS m/z (M + H⁺)570.0. 879 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-[3-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 570.0. 8806-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-[4-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 570.0.

Example 23a

2-Benzyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline,Cpd 680

A solution of Cpd 916 (50 mg, 0.121 mmol) and benzaldehyde 23a (0.014mL, 0.134 mmol) in CH₂Cl₂ (2 mL) was stirred at room temperature for 30min Sodium triacetoxyborohydride (38.6 mg, 0.182 mmol) was added and themixture was stirred overnight. The resulting mixture was combined withCH₂Cl₂ and H₂O, and pH of the water layer was adjusted to pH˜8with 1Naqueous NaOH. The organic solution was dried over Na₂SO₄ andconcentrated. Purification the residue by flash column chromatography(silica gel, 2% MeOH/EtOAc) gave Cpd 680 (38.6 mg). ¹H NMR (400 MHz,CDCl₃): δ 7.89 (d, J=3.2 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.32-7.44 (m,6H), 7.3 (d, J=8.1 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 4.33-4.63 (m, 2H),3.99-4.34 (m, 4H), 3.75-3.98 (m, 2H), 3.70 (s, 2H), 3.65 (s, 2H),3.16-3.30 (m, 1H), 2.93 (t, J=5.7 Hz, 2H), 2.76 (t, J=5.7 Hz, 2H),2.37-2.60 (m, 4H). MS m/z (M+H⁺) 502.0.

Following the procedure described above for Example 23a, andsubstituting the appropriate reagents, starting materials, andpurification methods known to those skilled in the art, the followingcompounds of the present invention were prepared:

Cpd Cpd Name and Data 14582-Benzyl-8-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M +H⁺) 502.3

Example 24

1-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline,Cpd 372

To a dry Schlenk tube was added a mixture of compound l1 (30 mg; 0.0073mmol), palladium (II) acetate (1 mg; 0.00037 mmol), BINAP (3 mg; 0.00044mmol), and KO^(t)Bu (12 mg; 0.01 mmol). The tube, equipped with ateflon-lined septum, was evacuated, and filled with argon. Bromobenzene(14 mg; 0.0088 mmol), and toluene (0.8 mL) were added to the reactionmixture via syringe. The reaction mixture was heated at 110° C. for 21h. The resultant mixture was diluted with CH₂Cl₂, and washedsequentially with saturated NH₄Cl _((aq)) and H₂O. The organic phase wasdried over Na₂SO₄, filtered, and concentrated. Purification of theresidue by preparative TLC (silica gel, 2% MeOH/EtOAc+0.5% Et₃N) gavecompound 372 (1.3 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J=3.3 Hz,1H), 7.55 (d, J=3.0 Hz, 1H), 7.36-7.45 (m, 3H), 7.14-7.26 (m, 4H), 6.55(d, J=8.6 Hz, 1H), 3.98-4.64 (m, 6H), 3.74-3.96 (m, 2H), 3.61-3.72 (m,2H), 3.16-3.27 (m, 1H), 2.88 (t, J=6.3 Hz, 2H), 2.37-2.61 (m, 4H),2.05-2.13 (m, 2H); LC/MS m/z (M+H⁺) 488.0.

Following the procedure described above for Example 24 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 3736-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1,2,3,4- tetrahydroquinoline¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J = 3.3 Hz, 1H), 7.60 (d, J = 8.3Hz, 2H), 7.55 (d, J = 3.0 Hz, 1H), 7.46 (s, 1H), 7.33 (d, J = 8.3 Hz,2H), 7.24 (dd, J = 8.7, 2.1 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 4.01-4.62(m, 6H), 3.75-3.98 (m, 2H), 3.64-3.73 (m, 2H), 3.18-3.30 (m, 1H), 2.87(t, J = 6.3 Hz, 2H), 2.36-2.62 (m, 4H), 2.02-2.12 (m, 2H); LC/MS m/z(M + H⁺) 556.0. 3746-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[3-(trifluoromethyl)phenyl]-1,2,3,4- tetrahydroquinoline¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J = 3.0 Hz, 1H), 7.55 (d, J = 3.0Hz, 1H), 7.37-7.52 (m, 5H), 7.22 (dd, J = 8.6, 2.0 Hz, 1H), 6.66 (d, J =8.6 Hz, 1H), 4.03-4.59 (m, 6H), 3.74-3.96 (m, 2H), 3.61-3.72 (m, 2H),3.18-3.27 (m, 1H), 2.89 (t, J = 6.3 Hz, 2H), 2.37-2.60 (m, 4H),2.03-2.14 (m, 2H); LC/MS m/z (M + H⁺) 556.0. 3751-Pyrimidin-2-yl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline ¹H NMR (400MHz, CDCl₃): δ 8.46 (d, J = 4.8 Hz, 2H), 7.89 (d, J = 3.0 Hz, 1H), 7.83(d, J = 8.6 Hz, 1H), 7.55 (d, J = 3.3 Hz, 1H), 7.50 (s, 1H), 7.41 (dd, J= 8.6, 2.0 Hz, 1H), 6.75 (t, J = 4.8 Hz, 1H), 4.06-4.61 (m, 6H),3.99-4.06 (m, 2H), 3.77-3.96 (m, 2H), 3.18-3.29 (m, 1H), 2.83 (t, J =6.4 Hz, 2H), 2.39-2.59 (m, 4H), 1.99-2.07 (m, 2H); LC/MS m/z (M + H⁺)490.0. 883 2-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M +H⁺) 488.1 6682-Pyrimidin-2-yl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M +H⁺) 490.0 6612-Pyridin-2-yl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M +H⁺) 489.0 805 2-Phenyl-8-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M +H⁺) 490.1

Example 25

A. 1-Acetyl-6-bromo-1,2,3,4-tetrahydro-quinoline-2-carboxylic acidmethyl ester, 25b

To a solution of compound 25a (100 mg, 0.37 mmol) in CH₂Cl₂ (5 mL) wasadded acetyl chloride (0.1 mL), and pyridine (0.1 mL). The reactionmixture was stirred at room temperature for 2 h. The resultant mixturewas partitioned between CH₂Cl₂ and H₂O. The organic phase was dried overNa₂SO₄, filtered, and concentrated to give the crude compound 25b (116mg), which was used in the next step without further purification. LC/MSm/z 312.0 (M+H⁺), 314.0 (M+2H⁺).

B. 1-Acetyl-6-bromo-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid, 25c

To a solution of compound 25b (116 mg, 0.37 mmol) in THF/MeOH/H₂O (2/2/2mL) was added LiOH (62 mg, 1.48 mmol). The reaction mixture was stiffedat room temperature for 3 h. The resultant mixture was concentratedunder reduced pressure, partitioned between CH₂Cl₂ and H₂O, and theaqueous phase was brought to pH 5 by the addition of 2N HCl (aq). Theorganic phase was dried over Na₂SO₄, filtered, and concentrated underreduced pressure to give the crude compound 25c, which was used in thenext step without further purification. LC/MS m/z 298.0 (M+H⁺), 300.0(M+2H⁺).

C.1-Acetyl-6-bromo-2-({3-[4-(trifluoroacetyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline,25d

To a solution of compound 1g (228 mg, 0.74 mmol), compound 25c (22 mg,0.74 mmol), and Et₃N (0.3 mL, 2.22 mmol) in CH₂Cl₂ (7 mL) was added HATU(338 mg, 0.89 mmol). The reaction mixture was stirred at roomtemperature for 18 h. The resultant mixture was diluted with CH₂Cl₂ andwashed with aqueous NaHCO₃. The organic phase was dried over Na₂SO₄,filtered, and concentrated under reduced pressure. Purification of theresidue by flash column chromatography (silica gel, 2% MeOH/EtOAc+0.5%Et₃N) gave compound 25d (265 mg). LC/MS m/z (M+H⁺), 517.0 (M+2H⁺),519.0.

D.1-Acetyl-6-bromo-2-({3-[piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline,25e

To a solution of compound 25d (261 mg, 0.505 mmol) in MeOH (3 mL) wasadded K₂CO₃ (140 mg, 1.01 mmol). The reaction mixture was stirred atroom temperature for 30 min. The resultant mixture was filtered, thefiltrate concentrated under reduced pressure, and the resultant residuepartitioned between CH₂Cl₂ and H₂O. The organic phase was dried overNa₂SO₄, filtered, and concentrated under reduced pressure to givecompound 25e (158 mg). LC/MS m/z (M+H⁺) 421.0, (M+2H⁺) 423.0.

E.1-Acetyl-6-bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline,Cpd 376

The title compound was prepared in an analogous manner to that ofcompound 357 substituting compound 25e for compound 20c. LC/MS m/z(M+H⁺) 532.0, (M+2H⁺) 534.0.

Following the procedure described above for Example 25 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 377 1-Acetyl-6-bromo-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline LC/MS m/z (M + H⁺) 532.0, (M + 2H⁺) 534.0. 3781-Acetyl-6-bromo-2-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline LC/MS m/z (M +H⁺) 525.0, (M + 2H⁺) 527.0.

Example 26

A. tert-Butyl 3-(4-Benzoyl-piperazin-1-yl)-azetidine-1-carboxylate, 4b

To a solution of compound 2a (5g) and compound 4a (6.75 g) in 1,2dichloroethane (50 mL) was added AcOH (1.0 mL) and 4 Å molecular sieves.The resultant mixture was stirred for 2 h, at which time NaBH(OAc)₃(11g) was added in three portions. The mixture was stirred for 18 h,poured into 2N KOH (aq., 50 mL), and then extracted with EtOAc (3×). Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure reduced pressure. The residue waspurified by flash column chromatography (5% MeOH/CH₂Cl₂) to givecompound 4b (11.6 g).

B. 3-(4-Benzoyl-piperazin-1-yl)-azetidine, HCl salt 2c

To a solution of compound 4b (5.1 g) in CH₂Cl₂ (20 mL) was added TFA (10mL). The resultant mixture was stirred at room temperature for 4 h. Thesolvents were removed under reduced pressure. The resultant residue wasdissolved in CH₂Cl₂ (5 mL), to which was added 4M HCl in dioxane (3.67mL). The resulting solid was collected by filtration, washed with ether,and dried under reduced pressure to give compound 2c as itshydrochloride salt (4.0 g).

C. 4-Acetoxy benzoyl chloride, 26b

To a solution of compound 26a (200 mg, 1.11 mmol) in THF (5 mL) wasadded oxalyl dichloride (97 μL, 1.11 mmol) dropwise at 0° C., followedby the addition of 2 drops of DMF. The resultant mixture was stiffed at0° C. for 3 h, and then warmed to room temperature for 18 h. Thesolvents were removed under reduced pressure and the crude residue,compound 26b, was dried under reduced pressure for 2 h, and used in thenext step without further purification.

D. 4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenylacetate (26c)

To a mixture of the HCl salt of compound 2c (373 mg, 1.33 mmol), Et₃N(0.5 mL) and CH₂Cl₂ (5 mL) was added a solution of compound 26b inCH₂Cl₂ (1 mL). The resultant mixture was stirred at room temperature for4 h. The solvent was removed under reduced pressure, the residuedissolved in CH₂Cl₂ (1 mL), and then purified by flash columnchromatography (silica gel, 5% MeOH/CH₂Cl₂) to give compound 26c (442mg).

E.4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenol,26d

A mixture of compound 26c (420 mg, 1.03 mmol) and LiOH (100 mg, 4.0mmol) in a solvent mixture of THF/MeOH/H₂O (2/2/2 mL) was stirred atroom temperature for 4 h, at which time it was brought to pH 5 by theaddition of 2N HCl (aq). The mixture was extracted with EtOAc (3×). Thecombined extracts were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The resultant residue (crude compound 26d) wasdried under reduced pressure for 18 h, and used in the following stepwithout further purification.

F.1-[1-({4-[(3,4-dichlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine,Cpd 379

A mixture of compound 26d (70 mg, 0.191 mmol), K₂CO₃ (53 mg, 0.382mmol), compound 26e (68 mg, 0.287 mmol) and DMF (3 mL) was stirred atroom temperature for 18 h. Water was added to the reaction mixture andthe mixture was extracted with EtOAc (3×). The combined organic extractswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The resultant residue was purified by flash columnchromatography, eluting with 5% MeOH/CH₂Cl₂ to give compound 379 (83mg). ¹H NMR (CDCl₃): δ 7.59-7.64 (d, J=8.8 Hz, 2H), 7.53 (d, J=2.0 Hz,1H), 7.455 (d, J=8.0 Hz, 1H), 7.37-7.44 (m, 5H), 7.23-7.28 (m, 2H),6.955 (d, J=8.84 Hz, 2H), 5.05 (s, 2H), 4.31 (br. s., 1H), 4.11-4.27 (m,2H), 4.00-4.10 (m, 1H), 3.91 (br. s., 1H), 3.64-3.82 (m, 1H), 3.48 (br.s., 2H), 3.18-3.27 (m, 1H), 2.42 (br. s., 4H). MS m/z (M+H⁺) 524.0.

Following the procedure described above for Example 26 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 3801-(1-{[4-(Naphthalen-2-ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.80-7.88 (m, 4H),7.59-7.64 (m, J = 8.8 Hz, 2H), 7.45-7.53 (m, 3H), 7.36-7.43 (m, 5H),7.00 (d, J = 8.8 Hz, 2H), 5.22 (s, 2H), 4.24-4.32 (m, 1H), 4.08-4.24 (m,2H), 4.03 (br. s., 1H), 3.60-3.79 (m, 1H), 3.31-3.52 (m, 2H), 3.10-3.22(m, 1H), 2.38 (br. s., 4H). MS m/z (M + H⁺) 506.2 3811-[1-({4-[(2,3-Dichlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.625 (d, J = 8.4 Hz,2H), 7.44 (dd, J = 8.0, 2.1 Hz, 2H), 7.37-7.41 (m, 5H), 7.23 (t, J =8.1, 1H), 6.97 (d, J = 8.8 Hz, 2H), 5.18 (s, 2H), 4.26-4.36 (m, 1H),4.12-4.26 (m, 2H), 4.07 (br. s, 1H), 3.88 (br. s., 1H), 3.74 (br. s.,1H), 3.47 (br. s., 2H), 3.14-3.27 (m, 1H), 2.41 (br. s., 3H), 2.22 (s,1H). MS m/z (M + H⁺) 524.0 3821-[1-({4-[(4-Fluorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 474.2 3831-(Phenylcarbonyl)-4-{1-[(4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)carbonyl]azetidin-3- yl}piperazine MSm/z (M + H⁺) 524.2 3841-[1-({4-[(4-Chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 490.2 3851-[1-({4-[(2,4-Dichlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 524.1 3864-{[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]methyl}benzonitrile MS m/z (M + H⁺) 481.2 3871-[1-({4-[2-(4-Chlorophenyl)ethoxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 504.2 3881-[1-({4-[2-(4-Fluorophenyl)ethoxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 488.2 3891-(Phenylcarbonyl)-4-(1-{[4-({4-[(trifluoromethyl)sulfanyl]benzyl}oxy)phenyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 556.2 3901-(Phenylcarbonyl)-4-{1-[(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)carbonyl]azetidin-3- yl}piperazineMS m/z (M + H⁺) 540.2 3911-[1-({4-[(3-Chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 490.2 3921-[1-({4-[(3-Chloro-4-fluorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 508.2 3931-(Phenylcarbonyl)-4-{1-[(4-{[3-(trifluoromethoxy)benzyl]oxy}phenyl)carbonyl]azetidin-3- yl}piperazineMS m/z (M + H⁺) 540.2 3944-[(4-{[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]methyl}phenyl)sulfonyl]morpholine MS m/z (M + H⁺)605.2 395 1-{1-[(4-{[3-Fluoro-4-(trifluoromethyl)benzyl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 542.2 3961-(Phenylcarbonyl)-4-(1-{[4-(pyridin-4-ylmethoxy)phenyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 457.2

Example 27

A. Methyl 4-(3-chlorobenzyloxy)-3-chlorobenzoate, 27c

A mixture of compound 27a (500 mg, 2.7 mmol), compound 27b (0.53 mL,4.03 mmol), and K₂CO₃ (745 mg, 5.4 mmol) in DMF was stirred at roomtemperature for 18 h. Water was added to the reaction mixture and themixture was extracted with EtOAc (3×). The combined organic extractswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The resultant residue was purified by silica gel flash columnchromatography, eluting with 30% EtOAc/hexanes to give compound 27c (662mg).

B. 4-(3-Chlorobenzyloxy)-3-chlorobenzoic acid, 27d

A mixture of compound 27c (662 mg, 2.0 mmol) and LiOH (192 mg, 8 mmol)in a solvent mixture of THF/MeOH/H₂O (3/3/3 mL) was stirred at roomtemperature for 4 h, then acidified with 15% citric acid in H₂O. Themixture was extracted with EtOAc (3×), and the combined extracts washedsequentially with water and brine. The extracts were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The resultant crudecompound 3b was dried under reduced pressure for 18 h and used in thefollowing reaction without further purification.

C. 4-(3-Chlorobenzyloxy)-3-chlorobenzoyl chloride, 27e

To a solution of compound 27d (67 mg, 0.33 mmol) in THF (2 mL) was addedoxalyl dichloride (43 μL, 0.50 mmol) dropwise at 0° C., followed by theaddition of 2 drops of DMF. The resultant mixture was stirred at 0° C.for 3 h, and then was warmed up to room temperature over 18 h. Thesolvents were removed under reduced pressure. The resultant residue,crude compound 27e, was dried under reduced pressure for 2 h and used inthe following step without further purification.

D.1-[1-({3-Chloro-4-[(3-chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine,Cpd 397

To a mixture of compound 2c (84 mg, 0.30 mmol), Et₃N (0.5 mL), andCH₂Cl₂ (2.5 mL) was added a solution of compound 27e in CH₂Cl₂ (1 mL).The resultant mixture was stirred at room temperature for 4 h. Thesolvent was removed under reduced pressure. The resultant residue wasdissolved in CH₂Cl₂ (1 mL), loaded on a silica gel column, and purifiedby flash column chromatography, eluting with 5% MeOH/CH₂Cl₂ to givecompound 397 (32 mg). ¹H NMR (CDCl₃): δ 7.695 (d, 1H, J=2.0 Hz), 7.515(dd, 1H, J=2.0 Hz, J2=8.6 Hz), 7.44 (s, 1H), 7.38-7.43 (m, 5H),7.30-7.35 (m, 3H), 6.91-6.97 (d, 1H, J=8.6 Hz), 5.15 (s, 2H), 4.26-4.37(m, 1H), 4.15-4.26 (m, 2H), 3.84-3.98 (m, 1H), 3.68-3.82 (m, 1H), 3.48(br. s., 2H), 3.18-3.29 (m, 1H), 2.56-2.16 (m, 4H). MS m/z (M+H⁺) 524.0.

Following the procedure described above for Example 27 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 398 1-(1-{[3-Chloro-4-(pyridin-4-ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 8.64 (d, J = 5.8 Hz, 2H), 7.2(d, J = 2.0 Hz, 1H), 7.53 (dd, J1 = 2.1, 8.4 Hz, 1H), 7.36-7.45 (m, 7H),6.88-6.95 (d, J = 8.6 Hz, 1H), 5.19 (s, 2H), 4.27-4.37 (m, 1H),4.11-4.27 (m, 2H), 3.99-4.08 (m, 1H), 3.81-3.96 (m, 1H), 3.73 (br. s,1H), 3.48 (br. s., 2H), 3.17-3.30 (m, 1H), 2.41 (br. s., 4H). MS m/z(M + H⁺) 498.0 399 1-[1-({3-Chloro-4-[(3,4-dichlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.70 (d, J = 2.0 Hz, 1H),7.56 (s, 1H), 7.53 (dd, J = 8.6, 2.0 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H),7.37-7.44 (m, 5H), 7.28-7.32 (m, 1H), 6.93 (d, J = 8.2 Hz, 1H), 5.14 (s,2H), 4.28-4.37 (m, 1H), 4.12-4.27 (m, 2H), 4.05 (br. s., 1H), 3.91 (br.s., 1H), 3.74 (br. s., 1H), 3.49 (br. s., 2H), 3.16-3.27 (m, 1H), 2.42(br. s., 4H). MS m/z (M + H⁺) 558.0 4001-[1-({4-[(3,4-Dichlorobenzyl)oxy]-3fluorophenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H),7.53-7.57 (m, 2H), 7.41-7.48 (m, 2H), 7.39 (dd, J = 8.5, 1.1 Hz, 1H),7.25-7.30 (m, 1H), 6.97 (t, J = 8.3 Hz, 1H), 5.12 (s, 2H), 4.52 (br. d.,J = 33.8 Hz, 1H), 4.37-4.47 (m, 1H), 4.32 (d, J = 6.8 Hz, 1H), 4.15-4.28(m, 2H), 4.07 (d, J = 8.3 Hz, 1H), 3.85 (d, J = 17.4 Hz, 2H), 3.20-3.28(m, 1H), 2.48 (t, J = 4.8 Hz, 4H). MS m/z (M + H⁺) 549.0. 4011-[1-({3-Chloro-4-[(3-chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.3 Hz,1H), 7.71 (d, J = 2.0 Hz, 1H), 7.50-7.57 (m, 2H), 7.45 (s, 1H),7.30-7.35 (m, 3H), 6.95 (d, J = 8.6 Hz, 1H), 5.17 (s, 2H), 4.43 (br. s.,1H), 4.28-4.38 (m, 1H), 4.17-4.28 (m, 1H), 4.03-4.15 (m, 2H), 3.85 (d, J= 19.5 Hz, 2H), 3.19-3.29 (m, 1H), 2.48 (m, 4H). MS m/z (M + H⁺) 531.0402 1-(1-{[3-Chloro-4-(pyridin-3-ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 8.71 (s, 1H), 8.61 (d, J = 3.5Hz, 1H), 7.88 (d, J = 3.0 Hz), 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.72 (d, J= 2.3 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 3.6 Hz, 1H), 7.36(dd, J = 7.8, 4.8 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 5.21 (s, 2H), 4.52(br. S, 1H), 4.43 (br. S, 1H), 4.32 (m, 1H), 4.16-4.29 (m, 2H),4.03-4.16 (m, 1H), 3.76-3.95 (m, 2H), 3.20-3.30 (m, 1H), 2.57-2.36 (m,4H). MS m/z (M + H⁺) 498.0. 4031-(1-{[4-(Pyridin-4-ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 8.63 (d, J =5.8 Hz, 2H), 7.88 (d, J = 3.0 Hz, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.55(d, J = 3.3 Hz, 1H), 7.36 (d, J = 6.1 Hz, 2H), 6.96 (d, J = 8.84 Hz,2H), 5.14 (s, 2H), 4.52 (br. s, 1H), 4.43 (br. s, 1H), 4.36-4.29 (m,1H), 4.16-4.29 (m, 2H), 4.04-4.16 (m, 1H), 3.75-3.93 (m, 2H), 3.18-3.28(m, 1H), 2.37-2.58 (m, 4H). MS m/z (M + H⁺) 464.0 4041-[1-({3-Chloro-4-[(3,4-dichlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.0 Hz,1H), 7.71 (d, J = 2.0 Hz, 1H), 7.51-7.58 (m, 3H), 7.47 (dd, J = 8.3, 4.0Hz, 1H), 7.30 (dd, J = 8.1, 2.0 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 5.14(s, 2H), 4.52 (br. s., 1H), 4.37 (br. s., 1H), 4.29-4.37 (m, 1H), 4.22(br. s., 2H), 4.01-4.14 (m, 1H), 3.88 (br. s., 2H), 3.19-3.32 (m, 1H),2.40-2.55 (m, 4H) MS m/z (M + H⁺) 564.6, 566.8 4051-[1-({4-[(2,3-Dichlorobenzyl)oxy]-3-fluorophenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H), 7.55(d, J = 3.3 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.43-7.46(m, 1H), 7.40 (dd, J = 8.6, 1.3 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.25(d, J = 7.8 Hz, 1H), 7.00 (t, J = 8.3 Hz, 1H), 5.28 (s, 2H), 4.49 (d, J= 33.2 Hz, 2H), 4.31-4.39 (m, 1H), 4.22 (br. s., 2H), 4.03-4.16 (m, 1H),3.88 (br. s., 2H), 3.19-3.31 (m, 1H), 2.40-2.58 (m, 4H). MS m/z (M + H⁺)549.0 406 1-(1-{[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine¹H NMR (CDCl₃): δ 8.59 (d, J = 4.5 Hz, 1H), 7.76 (dd, J = 1.5, 7.6 Hz,1H), 7.73 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.50 (dd, J =8.6, 2.0 Hz, 1H), 7.37-7.44 (m, 5H), 7.25 (dd, J = 6.9, 5.2 Hz, 1H),7.00 (d, J = 8.6 Hz, 1H), 5.28-5.35 (m, 2H), 4.27-4.37 (m, 1H),4.12-4.27 (m, 2H), 3.99-4.12 (m, 1H), 3.89 (br. s., 1H), 3.74 (br. s.,1H), 3.47 (br. s., 2H), 3.17-3.27 (m, 1H), 2.42 (br. s., 3H), 2.27 (br.s., 1H). 407 1-(1-{[3-Chloro-4-(pyridine-2-ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 8.54 (br. s, 1H), 8.49 (br. s,1H), 7.62-7.68 (m, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.37-7.44 (m, 5H),7.29 (d, J = 9.1 Hz, 2H), 7.23 (dd, J = 7.8, 4.8 Hz, 1H), 4.17-4.32 (m,2H), 4.09-4.17 (m, 3H), 4.00-4.08 (m, 1H), 3.89 (br. s., 1H), 3.74 (br.s, 1H), 3.47 (br. s, 2H), 3.15-3.28 (m, 1H), 2.41 (br. s., 3H), 2.17(br. s, 1H) MS m/z (M + H⁺) 498.0 408 1-(1-{[3-Chloro-4-(pyridin-4-ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazineMS m/z (M + H⁺) 491.2 409 1-(1-{[3-Chloro-4-(pyridin-3-ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazineMS m/z (M + H⁺) 491.2 481 1-[1-({4-[(4-Chlorobenzyl)oxy]-3-fluorophenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MSm/z (M + H⁺) 508.2 482 1-[1-({4-[(3,4-Dichlorobenzyl)oxy]-3-fluorophenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MSm/z (M + H⁺) 542.1 483 1-[1-({4-[(2,3-Dichlorobenzyl)oxy]-3-fluorophenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MSm/z (M + H⁺) 542.1 484 1-[1-({4-[(4-Chlorobenzyl)oxy]-3-iodophenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z(M + H⁺) 616.1 972 1-[1-({4-[(5-Chlorothiophen-2-yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazineMS m/z (M + H⁺) 496.0 5602-{[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]methyl}quinoline MS m/z (M + H⁺) 507.0 5521-[1-({4-[(6-Bromopyridin-2-yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazineMS m/z (M + H⁺) 535.0 9571-[1-({4-[(3-Chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 497.0 9621-[1-({4-[(5-Chlorothiophen-2-yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 503.0 9672-{[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]methyl}quinoline MS m/z (M + H⁺) 514.0 9831-[1-({4-[(6-Bromopyridin-2-yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 543.8 9601-[1-({4-[(3-Chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 497.0 9631-[1-({4-[(5-Chlorothiophen-2-yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 503.0 9702-{[4-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]methyl}quinoline MS m/z (M + H⁺) 514.0 9871-[1-({4-[(6-Bromopyridin-2-yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 542.0

Example 27a

E. Methyl 4-((5-chloropyridin-3-yl)methoxy)benzoate, 27b

DIAD (2.35 mmol, 0.45 mL) was added to an ice-cold solution of methyl4-hydroxybenzoate 29a (2.35 mmol, 358 mg),(5-chloropyridin-3-yl)methanol 27a (1.57 mmol, 225 mg), and Ph₃P (2.35mmol, 616 mg) in 8 mL of THF. The mixture was stirred at 0° C. for 1 hat room temperature overnight. Water was added and the crude product waspurified by flash column chromatography (silica gel, 20% EtOAc/hexanes)to afford 300 mg (68%) of 27b.

F. 4-((5-Chloropyridin-3-yl)methoxy)benzoic acid, 27c

Compound 27b (1.22 mmol, 340 mg) was combined with LiOH (4.9 mmol, 118mg) in 3 mL of THF, 3 mL of MeOH, and 3 mL of water. The mixture wasstirred at room temperature for 4 h and was then combined with 15%aqueous citric acid and extracted with EtOAc. The extracts were washedwith water and brine, dried over Na₂SO₄, and concentrated under vacuumto give 288 mg of 27c.

Following the procedure described above for Example 1 or Example 27, andsubstituting the appropriate reagents, starting materials andpurification methods known to those skilled in the art, the followingcompounds of the present invention were prepared:

Cpd Cpd Name and Data 554 1-[1-({4-[(5-Chloropyridin-3-yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazineMS m/z (M + H⁺) 491.0 978 1-[1-({4-[(5-Chloropyridin-3-yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 498.0 9811-[1-({4-[(5-Chloropyridin-3-yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 498.0

Example 27b

Following the procedure described above for Example 1c, and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Salt Cpd Cpd Name and Data Form 958 1-[1-({4-[(3- N-TFAChlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(trifluoroacetyl)piperazine MS m/z (M + H⁺) 482.0 9611-[1-({4-[(5-Chlorothiophen-2- N-TFAyl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4- (trifluoroacetyl)piperazineMS m/z (M + H⁺) 488.0 968 2-{[4-({3-[4-(Trifluoroacetyl)piperazin-1-N-TFA yl]azetidin-1- yl}carbonyl)phenoxy]methyl}quinoline MS m/z (M +H⁺) 499.0 979 1-[1-({4-[(5-Chloropyridin-3- N-TFAyl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4- (trifluoroacetyl)piperazine984 1-[1-({4-[(6-Bromopyridin-2- N-TFAyl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4- (trifluoroacetyl)piperazineMS m/z (M + H⁺) 535.0

Example 28

A. Methyl 4-(3-chlorobenzylsulfanyl)benzoate, 28b

The title compound 28c was prepared using the method described inExample 27, substituting compound 28a for compound 27a in Procedure A.

B. 4-(3-Chlorobenzylsulfanyl)benzoic acid, 28c

The title compound 28c was prepared using the method described inExample 27, substituting compound 28b for compound 27c in Procedure B.

C. 4-(3-Chlorobenzylsulfanyl)benzoyl chloride, 28d

The title compound 28d was prepared using the method described inExample 27, substituting compound 28c for compound 27d in Procedure C.

D.1-[1-({4-[(3-Chlorobenzyl)sulfanyl]phenyl}carbonyl)azetidi-3-yl]-4-(phenylcarbonyl)piperazine,Cpd 410

The title compound 410 was prepared using the method described inExample 27, substituting compound 28d for compound 27e in Procedure D.¹H NMR (CDCl₃): δ 7.52 (d, J=8.6 Hz, 2H), 7.37-7.44 (m, 5H), 7.24-7.29(m, 3H), 7.18-7.24 (m, 3H), 4.18-4.33 (m, 2H), 4.09-4.17 (m, 3H),4.01-4.08 (m, 1H), 3.92 (br. S, 1H), 3.74 (br. s., 1H), 3.35-3.63 (m,2H), 3.17-3.29 (m, 1H), 2.20-2.50 (m, 4H); MS m/z (M+H⁺) 506.0.

Following the procedure described above for Example 28 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 411 1-[1-({4-[(2,3-Dichlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.52 (d, J = 8.3 Hz, 2H),7.38-7.43 (m, 5H), 7.29 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 7.1 Hz, 1H),7.2 (d, J = 7.4 Hz, 1H), 7.11 (q, J = 7.8 Hz, 1H), 4.24-4.38 (m, 4H),4.22 (br. s., 1H), 4.12-4.21 (m, 1H), 4.02-4.12 (m, 1H), 3.91 (br. s.,1H), 3.77 (br. s., 1H), 3.47 (s, 2H), 3.15-3.29 (m, 1H), 2.44 (br. s.,4H). MS m/z (M + H⁺) 540.0 4121-[1-({4-[(3-Chlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d,J = 3.3 Hz, 1H), 7.49-7.57 (m, 3H), 7.25-7.30 (m, 3H), 7.18-7.25 (m,3H), 4.51 (br. s., 2H), 4.21-4.34 (m, 2H), 4.03-4.21 (m, 4H), 3.72-3.94(m, 2H), 3.18-3.29 (m, 1H), 2.35-2.59 (m, 4H). MS m/z (M + H⁺) 513.0 4131-[1-({4-[(2,3-Dichlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.0Hz, 1H), 7.50-7.57 (m, 3H), 7.38 (dd, J = 7.8, 1.5 Hz, 1H), 7.26-7.33(m, 3H), 7.22 (dd, J = 7.7, 1.4 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 4.44(br. d., J = 32.6 Hz, 2H), 4.22-4.35 (m, 4H), 4.15-4.22 (m, 1H),4.04-4.15 (m, 1H), 3.85 (d, J = 17.4 Hz, 2H), 3.19-3.29 (m, 1H),2.37-2.56 (m, 4H). MS m/z (M + H⁺) 547.0. 414 1-[1-({4-[(3,4-Dichlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.3Hz, 1H), 7.54 (d, J = 3.3 Hz, 2H), 7.51-7.53 (m, 1H), 7.40 (d, J = 2.0Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.24-7.29 (m, 3H), 7.13-7.17 (m, 1H),4.48-4.59 (m, 1H), 4.35-4.48 (m, 1H), 4.20-4.34 (m, 2H), 4.13-4.20 (m,1H), 4.01-4.13 (m, 4H), 3.79-3.94 (m, 2H), 3.19-3.29 (m, 1H), 2.37-2.57(m, 4H). MS m/z (M + H⁺) 547.0. 4151-[1-({4-[(4-Chlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarboyl)piperazine ¹H NMR (CDCl₃): δ 7.87 (d, J= 3.3 Hz, 1H), 7.55 (d, J = 3.3 Hz, 1H), 7.53 (d, J = 8.6 Hz, 2H),7.27-7.29 (m, 2H), 7.24-7.27 (m, 4H), 4.51 (br. s., 1H), 4.35-4.47 (m,1H), 4.20-4.33 (m, 2H), 4.02-4.20 (m, 4H), 3.76-3.93 (m, 2H), 3.18-3.28(m, 1H), 2.38-2.54 (m, 4H). MS m/z (M + H⁺) 513.0 4161-[1-({4-[(Pyridin-3-ylmethyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 8.55 (s, 1H), 8.48 (s,1H), 7.82-7.93 (m, 1H), 7.65 (br. s., 1H), 7.47-7.60 (m, 3H), 7.18-7.36(m, 3H), 4.44 (d, J = 33.9 Hz, 2H), 4.03-4.32 (m, 5H), 3.86 (br. s.,2H), 3.23 (br. s., 1H), 2.47 (br. s., 4H) 417 1-[1-({4-[(3,4-Dichlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 540.1 4181-[1-({4-[(4-Chlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 506.2 5551-(Phenylcarbonyl)-4-[1-({4-[(pyridin-3-ylmethyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]piperazine MS m/z (M +H⁺) 473.0 550 1-(Phenylcarbonyl)-4-{1-[(4-{[3-(trifluoromethyl)benzyl]sulfanyl}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 540.0 9731-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{[3-(trifluoromethyl)benzyl]sulfanyl}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 547.0 9751-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(4-{[3-(trifluoromethyl)benzyl]sulfanyl}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 531.8

Example 28a

Following the procedure described above for Example 1c, and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Salt Cpd Cpd Name and Data Form 974 1-(Trifluoroacetyl)-4-{1-[(4-{[3-N-TFA (trifluoromethyl)benzyl]sulfanyl}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 532.0

Example 29

A. Methyl 4-(3-trifluoromethyl-phenoxy)-benzoate, 29c

To a solution of compound 29a (400 mg, 2.63 mmol) and compound 29b (1.0g, 5.26 mmol) in CH₂Cl₂ (24 mL) was added Cu(OAc)₂ (714 mg, 3.94 mmol),4A sieves (400 mg, powder, activated), pyridine (2 mL), and Et₃N (2 mL).The resultant reaction mixture was stirred at room temperature for 2days. Water was added to the mixture, and the mixture was filtered. Thefiltrate was extracted with EtOAc (3×), the combined organic extractsdried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by silica gel flash column chromatography,eluting with 20% EtOAc/hexanes to give compound 29c (470 mg).

B. 4-(3-Trifluoromethyl-phenoxy)-benzoic acid (29d)

A mixture of compound 29c (577 mg, 1.95 mmol) and LiOH (187 mg, 7.80mmol) in THF/MeOH/H₂O (4/4/4 mL) was stirred for 4 h. A 15% citric acidsolution (20 mL) was added, and the mixture was then extracted withEtOAc (3×). The combined extracts were washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residue,compound 29d, was dried under reduced pressure for 18 h and was usedwithout purification.

C. 4-(3-Trifluoromethyl-phenoxy)-benzoyl chloride, 29e

To a solution of compound 29d (100 mg, 0.35 mmol) in THF (2 mL) wasadded oxalyl dichloride (46 μL, 0.53 mmol) dropwise at 0° C., followedby addition of 2 drops of DMF. The resulting mixture was stiffed at 0°C. for 3 h, and was then warmed up to room temperature overnight. Thesolvents were removed under reduced pressure, and the residue, compound29e, was dried under reduced pressure for 2 h and then used in the nextstep without further purification.

D.1-(Phenylcarbonyl)-4-[1-({4-[3-(trifluoromethyl)phenoxy]phenyl}carbonyl)azetidin-3-yl]piperazine,Cpd 419

To a mixture of compound 2c (80 mg, 0.32 mmol), Et₃N (0.5 mL), andCH₂Cl₂ (2.5 mL) was added a solution of compound 29e in CH₂Cl₂ (1 mL).The resultant mixture was stiffed at room temperature for 4 h. Thesolvent was removed under reduced pressure, and the resultant residuewas dissolved in CH₂Cl₂ (1 mL), directly loaded onto a silica gelcolumn, and purified by silica gel flash column chromatography with 5%MeOH/CH₂Cl₂ to give compound 419 (53 mg). ¹H NMR (CDCl₃): δ 7.65 (d,J=8.6 Hz, 2H), 7.45-7.53 (m, 1H), 7.41 (br. s., 6H), 7.25-7.34 (m, 1H),7.17-7.25 (m, 1H), 7.01 (d, J=7.3 Hz, 2H), 4.17-4.38 (m, 3H), 4.11 (br.s., 1H), 3.92 (br. s., 1H), 3.78 (br. s., 1H), 3.49 (br. s, 2H),3.19-3.32 (m, 1H), 2.45 (br. s., 4H). MS m/z (M+H⁺) 510.0.

Following the procedure described above for Example 29 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 4201-(1-{[4-(4-Chlorophenoxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.0Hz, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 3.0 Hz, 1H), 7.33 (d, J= 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 4H), 4.52 (br. s., 1H), 4.38-4.48(br. S, 1H), 4.15-4.37 (m, 3H), 4.10 (br. s., 1H), 3.88 (br. s., 1H),3.82 (br. s., 1H), 3.19-3.31 (m, 1H), 2.35-2.60 (m, 4H). MS m/z (M + H⁺)483.1 421 1-(1-{[4-(3-Chlorophenoxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.3Hz, 1H), 7.65 (tt, J1 = 2 Hz, J2 = 8.8 Hz, 2H), 7.545 (d, J = 3.3 Hz,1H), 7.26-7.30 (m, 1H), 7.14 (dt, J = 8.1, 1.0 Hz, 1H), 6.98-7.06 (m,3H), 6.93-6.95 (m, 1H), 6.91-6.95 (m, 1H), 4.56 (br.s, 1H), 4.43 (br.s., 1H), 4.17-4.38 (m, 3H), 4.04-4.16 (m, 1H), 3.75-3.96 (m, 2H),3.20-3.31 (m, 1H), 2.39-2.60 (m, 4H). MS m/z (M + H⁺) 483.0 4221-(1-{[4-(3,4-Dichlorophenoxy)phenyl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine. ¹H NMR (CDCl₃): δ 7.65 (d, J = 8.6 Hz,2H), 7.37-7.46 (m, 6H), 7.12 (d, J = 2.8 Hz, 1H), 7.00 (d, J = 8.8 Hz,2H), 6.89 (dd, J = 8.8, 2.8 Hz, 1H), 4.16-4.37 (m, 3H), 4.10 (br. s.,1H), 3.92 (br. s., 1H), 3.68-3.84 (m, 1H), 3.46 (s, 2H), 3.19-3.30 (m,1H), 2.44 (br. s., 4H). MS m/z (M + H⁺) 510.0 4231-(1-{[4-(3,4-Dichlorophenoxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J =3.3 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 3.3 Hz, 1H), 7.42 (dJ = 8.8 Hz, 1H), 7.13 (d, J = 2.8 Hz, 1H), 7.0 (d, J = 8.6 Hz, 2H), 6.90(dd, J = 8.8, 2.8 Hz, 1H), 4.53 (br. s., 1H), 4.44 (br. S, 1H),4.17-4.38 (m, 3H), 4.11 (dd, J = 9.0, 4.7 Hz, 1H), 3.88 (br. s., 1H),3.83 (br. s., 1H), 3.20-3.32 (m, 1H), 2.50 (t, J = 4.7 Hz, 4H). MS m/z(M + H⁺) 517.0 424 1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[3-(trifluoromethyl)phenoxy]phenyl}carbonyl)azetidin-3- yl]piperazine ¹HNMR (CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.55(d, J = 3.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H),7.21 (d, J = 8.1 Hz, 1H), 7.03 (d, J = 8.6 Hz, 2H), 4.53 (br. s., 1H),4.44 (br. s, 1H), 4.17-4.38 (m, 3H), 4.16-4.05 (m, 1H), 3.86 (d, J =19.2 Hz, 2H), 3.20-3.33 (m, 1H), 2.37-2.60 (m, 4H). MS m/z (M + H⁺)517.0 425 1-(1-{[4-(4-Chlorophenoxy)phenyl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 476.2 4261-(1-{[4-(3-Chlorophenoxy)phenyl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 476.2 6621-(1-{[4-(3-Chlorophenoxy)-3-fluorophenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 500.8

Example 29a

Following the procedure described above for Example 1c, and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data Salt Form 931 1-(1-{[4-(3-Chlorophenoxy)-3- N-TFAfluorophenyl]carbonyl}azetidin-3-yl)-4- (trifluoroacetyl)piperazine MSm/z (M + H⁺) 485.8

Example 30

A. Methyl 4-(3-chloro-phenylsulfanyl)-benzoate (30c)

A mixture of compound 30a (400 mg, 1.86 mmol), compound 30b (321 mg,2.23 mmol), Pd(PPh₃)₄ (215 mg, 0.186 mmol), KOtBu (2.23 mL, 2.23 mmol,1M solution in THF), and THF (3.5 mL) were heated in a microwave reactorat 130° C. for 2 h, then poured into water (50 mL). The mixture wasextracted with EtOAc (3×). The combined organic extracts were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel flash column chromatography, eluting with 5%EtOAc/hexanes to give compound 30c (220 mg).

B. 4-(3-Chloro-phenylsulfanyl)benzoic acid (30d)

A mixture of compound 30c (320 mg, 1.15 mmol), LiOH (110 mg, 4.59 mmol)in THF/MeOH/H₂O (3/3/3 mL) was stirred for 4 h. A 15% aqueous citricacid solution (10 mL) was added. The mixture was then extracted withEtOAc (3×). The combined organic extracts were washed with brine,filtered, dried over Na₂SO₄, and concentrated under reduced pressure.The resultant residue (compound 30d, 290 mg) was dried under reducedpressure for 18 h and was used without further purification.

C.4-(1-{[4-(3-Chloro-phenylsulfanyl)phenyl]carbonyl}azetidin-3-yl)-1-(phenylcarbonyl)-piperazine,Cpd 427

A mixture of compound 30d (60 mg, 0.23 mmol), compound 2c (83 mg, 0.29mmol), and HATU (129 mg, 0.34 mmol) in Et₃N and DMF (1 mL/3 mL) wasstirred for 18 h, and then poured into water (10 mL). The mixture wasthen extracted with EtOAc (3×). The combined organic extracts werewashed with brine (2×), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The resultant residue was purified on silicagel, eluting with 5% MeOH/CH₂Cl₂ to give compound 427 (33 mg). MS m/z(M+H⁺) 492.1.

Following the procedure described above for Example 30 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 4281-[1-({4-[(3-Chlorophenyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 499.1 4291-[1-({4-[(3-Chlorophenyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 499.1 4301-(Phenylcarbonyl)-4-{1-[(4-{[3-(trifluoromethyl)phenyl]sulfanyl}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 526.2 4311-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{[3-(trifluoromethyl)phenyl]sulfanyl}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 533.1 4321-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(4-{[3-(trifluoromethyl)phenyl]sulfanyl}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 533.1

Example 30a

Following the procedure described above for Example 1c, and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Salt Cpd Cpd Name and Data Form 677 1-[1-({4-[(3- N-TFAChlorophenyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4-(trifluoroacetyl)piperazine MS m/z (M + H⁺) 483.8 7901-(Trifluoroacetyl)-4-{1-[(4-{[3- N-TFA(trifluoromethyl)phenyl]sulfanyl}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 517.9

Example 31

A. 4-(3-Chloro-benzensulfonyl)-benzoic acid methyl ester (31a)

To a solution of compound 30c (200 mg, 0.72 mmol) in CH₂Cl₂ (5 mL) wasadded mCPBA (320 mg, 1.43 mmol) at 0° C. After 2 h, the mixture waspoured into 2N KOH solution (20 mL) and extracted with EtOAc (3×). Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with 5% EtOAc/hexanes togive compound 31a (138 mg).

B. 4-(3-Chloro-benzensulfonyl)-benzoic acid (31b)

A mixture of compound 31a (138 mg, 0.44 mmol) and LiOH (42 mg, 1.77mmol) in THF/MeOH/H₂O (2/2/2 mL) was stirred for 4 h. A 15% citric acidsolution (10 mL) was added. The mixture was then extracted with EtOAc(3×). The combined organic extracts were washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultantresidue, compound 31b (130 mg) was dried under reduced pressure for 18 hand used without further purification.

C.1-[1-({4-[(3-Chlorophenyl)sulfonyl]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine,Cpd 433

A mixture of compound 31b (40 mg, 0.14 mmol), compound 2c (49 mg, 0.18mmol), and HATU (80 mg, 0.20 mmol) in Et₃N (1 mL) and DMF (2 mL) wasstirred for 18 h, and was then poured into water (10 mL). The mixturewas then extracted with EtOAc (3×). The combined organic extracts werewashed with brine (2×), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with 5% MeOH/CH₂Cl₂ to givecompound 428 (29 mg). MS m/z (M+H⁺) 524.1.

Following the procedure described above for Example 31, and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 508 1-(Phenylcarbonyl)-4-{1-[(4-{[3-(trifluoromethyl)phenyl]sulfonyl}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 558.0 876 1-[1-({4-[(3-Chlorophenyl)sulfonyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 530.8 6511-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{[3-(trifluoromethyl)phenyl]sulfonyl}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 564.8 15071-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(4-{[3-(trifluoromethyl)benzyl]sulfonyl}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 578.8 7381-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(4-{[3-(trifluoromethyl)phenyl]sulfonyl}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 564.6

Example 31a

Following the procedure described above for Example 31 and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Following the procedure described above for Example 31 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 976 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4-({[3-(trifluoromethyl)phenyl]sulfonyl}methyl)phenyl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (CDCl₃): δ 7.80-7.97 (m, 4H), 7.63-7.73 (m, 1H),7.56 (dd, J = 5.7, 2.4 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 4.34-4.60 (m,3H), 4.20-4.33 (m, 2H), 4.03-4.20 (m, 2H), 3.86 (br. s., 2H), 3.15-3.32(m, 1H), 2.37-2.60 (m, 4H), MS m/z (M + H⁺) 578.8 5641-(Phenylcarbonyl)-4-(1-{[4-({[3-(trifluoromethyl)phenyl]sulfonyl}methyl)phenyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 572.0 9711-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{[3-(trifluoromethyl)benzyl]sulfonyl}phenyl)carbonyl]azetidin-3-yl}piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H), 7.65-7.77(m, 4H), 7.52-7.65 (m, 2H), 7.35-7.52 (m, 2H), 7.24 (s, 1H), 4.39 (s,4H), 4.17-4.33 (m, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.86 (br. s., 2H),3.19-3.34 (m, 1H), 2.38-2.59 (m, 4H). MS m/z (M + H⁺) 578.8 9771-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[4-({[3-(trifluoromethyl)phenyl]sulfonyl}methyl)phenyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 578.6

Example 31b

D. 10-Oxidophenoxathiine-2-carboxylic acid, 31d

A mixture of phenoxathiine-2-carboxylic acid 31c (0.41 mmol, 100 mg) andsodium perborate tetrahydrate (0.82 mmol, 126 mg) in 3 mL of HOAc wasstiffed for 6 days at room temperature. TLC indicated 90% conversion to31d. Water was added and the resulting precipitate was filtered anddried to give 65 mg of 31d, 90% pure.

Following the procedure described above for Example 9 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 8071-{1-[(10-Oxidophenoxathiin-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 495.1

Example 31c

Following the procedure described above for Example 1c, and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compound of the presentinvention was prepared:

Salt Cpd Cpd Name and Data Form 9141-[1-({4-[(3-Chlorophenyl)sulfonyl]phenyl}- N-TFAcarbonyl)azetidin-3-yl]-4-(trifluoroacetyl)piperazine MS m/z (M + H⁺)516.8 1493 1-(Trifluoroacetyl)-4-{1-[(4-{[3- N-TFA(trifluoromethyl)phenyl]sulfonyl}phenyl)carbonyl]-azetidin-3-yl}piperazine MS m/z (M + H⁺) 550.5 14981-(Trifluoroacetyl)-4-(1-{[4-({[3- N-TFA(trifluoromethyl)phenyl]sulfonyl}methyl)phenyl]-carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 563.8

Example 32

tert-Butyl(3S)-3-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]pyrrolidine-1-carboxylate,Cpd 434

To a solution of compound 26d (100 mg, 0.273 mmol) and(R)—N-Boc-3-hydroxyproline in THF was added DIAD at 0° C. The resultingreaction mixture was stirred for 18 h. After dilution with water andextraction with EtOAc (3×), the combined organic extracts were driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresultant residue was purified by flash column chromatography on silicagel using 5% MeOH/CH₂Cl₂ to give compound 434 (95 mg). ¹H NMR (CDCl₃): δ7.52 (d, J=8.6 Hz, 2H), 7.37-7.44 (m, 5H), 7.24-7.29 (m, 3H), 7.18-7.24(m, 3H), 4.18-4.33 (m, 2H), 4.09-4.17 (m, 3H), 4.01-4.08 (m, 1H), 3.92(br. S, 1H), 3.74 (br. s., 1H), 3.35-3.63 (m, 2H), 3.17-3.29 (m, 1H),2.20-2.50 (m, 4H); MS m/z (M+H⁺) 506.0.

Following the procedure described above for Example 32 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 4351-(1-{[4-(Cyclohexyloxy)phenyl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.58 (d, J = 8.8 Hz, 2H),7.36-7.44 (m, 5H), 6.88 (d, J = 8.8 Hz, 2H), 4.26-4.38 (m, 2H),4.25-4.12 (m, 2H), 4.07 (br. s, 1H), 3.82-3.99 (m, 1H), 3.48 (br. s.,2H), 3.15-3.26 (m, 1H), 2.17-2.54 (m, 4H), 1.93-2.03 (m, 1H), 1.75-1.89(m, 2H), 1.46-1.63 (m, 2H), 1.31-1.46 (m, 3H), 1.21-1.31 (m, 2H). MS m/z(M + H⁺) 448.0 4361-(1-{[4-(Cyclopentyloxy)phenyl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 434.2 437 tert-Butyl4-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]piperidine-1- carboxylate MS m/z (M +H⁺) 549.3 438 tert-Butyl (3R)-3-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]pyrrolidine-1- carboxylate MS m/z (M +H⁺) 535.3

Example 33

A.(3S)-3-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]pyrrolidine,33a

To a solution of compound 434 (87.7 mg, 0.164 mmol) in CH₂Cl₂ (1 mL) wasadded TFA (0.5 mL). The resulting mixture was stirred at roomtemperature for 4 h. The reaction mixture was concentrated under reducedpressure to give compound 33a, which was used without furtherpurification.

B.(3S)—N,N-Dimethyl-3-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]pyrrolidine-1-sulfonamide,Cpd 439

A solution of compound 33a (0.164 mmol) and Et₃N (0.5 mL) in CH₂Cl₂ (2mL) was treated with N,N-dimethylsulfamoyl chloride (26 uL, 0.246 mmol)at room temperature. The resulting mixture was stirred for 3 h, and thesolvent was then removed under reduced pressure. The resultant residuewas directly loaded onto a silica gel column and was purified by silicagel flash column chromatography, eluting with 5% MeOH/CH₂Cl₂ to givecompound 439 (51.5 mg). ¹H NMR (CDCl₃): δ 7.61 (d, J=8.21 Hz, 2H),7.36-7.46 (m, 5H), 6.86 (d, J=8.6 Hz, 2H), 4.98 (m, 1H), 4.31 (br. s.,1H), 4.11-4.26 (m, 2H), 4.05 (br. s., 1H), 3.87-3.96 (m, 1H), 3.84 (m,1H), 3.70-3.79 (m, 1H), 3.66 (dd, J=11.4, 4.8 Hz, 1H), 3.39-3.58 (m,4H), 3.21-3.26 (m, 1H), 2.82 (s, 6H), 2.42 (br. s., 4H), 2.19-2.29 (m,2H); MS m/z (M+H⁺) 542.0.

Following the procedure described above for Example 33 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 4401-(Phenylcarbonyl)-4-{1-[(4-{[1-(phenylcarbonyl)piperidin-4-yl]oxy}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 553.3441 1-[1-({4-[(1-Acetylpiperidin-4-yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MSm/z (M + H⁺) 491.3 442 1-(Phenylcarbonyl)-4-{1-[(4-{[(3S)-1-(phenylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 539.3 4431-{1-[(4-{[(3R)-1-(Cyclohexylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MSm/z (M + H⁺) 545.3 444 1-(Phenylcarbonyl)-4-{1-[(4-{[(3R)-1-(phenylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 539.3 4451-{1-[(4-{[(3R)-1-(2,2-Dimethylpropanoyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MSm/z (M + H⁺) 519.3 446(3S)—N,N-Dimethyl-3-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]pyrrolidine-1-carboxamide MS m/z (M +H⁺) 506.3 447 1-(Phenylcarbonyl)-4-{1-[(4-{[(3S)-1-(pyrrolidin-1-ylsulfonyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin-3- yl}piperazineMS m/z (M + H⁺) 568.3 4481-(Phenylcarbonyl)-4-{1-[(4-{[(3S)-1-(pyrrolidin-1-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin-3- yl}piperazineMS m/z (M + H⁺) 532.3 4494-({(3S)-3-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]pyrrolidin-1-yl}carbonyl)morpholine MS m/z (M +H⁺) 548.3

Example 34

A. tert-Butyl3-(2-iodo-4-methoxycarbonyl-phenoxy)-pyrrolidine-1-carboxylate, 34b

To a solution of compound 34a (500 mg, 1.8 mmol), compound 32a (504 mg,2.7 mmol) and PPh₃ (707 mg, 2.7 mmol) in THF (10 mL) was added DIAD(0.52 mL, 2.7 mmol) at 0° C. The resulting mixture was stirred at 0° C.for 1 h, then warmed up to room temperature and stirred for 18 h. Themixture was poured into water and extracted with EtOAc (3×). Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography eluting with 50% EtOAc/hexanes to give compound34b (704 mg).

B. Methyl3-iodo-4-[1-(pyrrolidine-1-carbonyl)-pyrrolidin-3-yloxy]-benzoate, 34d

To a solution of compound 34b (210 mg, 0.47 mmol) in CH₂Cl₂ (3 mL) wasadded TFA (1.5 mL) at room temperature. The resulting mixture wasstirred at room temperature for 4 h. The solvent was removed underreduced pressure. The resultant residue was dried under reduced pressurefor 2 h. To the residue was added CH₂Cl₂ (3 mL) and Et₃N (1 mL),followed by the addition of compound 34c (77 μL, 0.7 mmol). Theresulting mixture was stirred for 2 h, then poured into water (50 mL)and extracted with EtOAc (3×). The combined organic extracts were driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by flash column chromatography, eluting with 80%EtOAc/hexanes to give compound 34d (180 mg).

C. 3-Iodo-4-[1-(pyrrolidine-1-carbonyl)-pyrrolidin-3-yloxy]-benzoicacid, 34e

A mixture of compound 34d (180 mg, 0.41 mmol), LiOH (39 mg, 1.62 mmol),THF (3 mL), MeOH (3 mL), and H₂O (3 mL) was stirred at room temperaturefor 4 h. The mixture was acidified with 15% aqueous citric acid andextracted with EtOAc (3×). The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The resultant residue was dried under reduced pressure for 2 hto give compound 34e (166 mg).

D. 3-Iodo-4-[1-(pyrrolidine-1-carbonyl)-pyrrolidin-3-yloxy]-benzoylchloride, 34f

To a solution of compound 34e (166 mg, 0.39 mmol) in THF (4 mL) wasadded oxalyl dichloride (43 μL, 0.50 mmol) dropwise at 0° C., followedby the addition of 2 drops of DMF. The resulting mixture was stirred at0° C. for 3 h, warmed to room temperature, and stirred for 18 h. Thesolvents were removed under reduced pressure. The resultant residue,compound 34f, was dried under reduced pressure for 2 h and used in thefollowing step without further purification.

E.1-{1-[(3-Iodo-4-{[(3S)-1-(pyrrolidin-1-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine,Cpd 450

To a mixture of compound 2c (61 mg, 0.25 mmol), Et₃N (0.5 mL), andCH₂Cl₂ (2.5 mL) was added a solution of compound 34f in CH₂Cl₂ (1 mL).The resulting mixture was stirred at room temperature for 2 h. Thesolvent was removed under reduced pressure. The residue was dissolved inCH₂Cl₂ (1 mL), directly loaded onto a silica gel column, and purified byflash column chromatography, eluting with 5% MeOH/CH₂Cl₂ to givecompound 451 (56 mg). ¹H NMR (CDCl₃): δ 8.06 (d, J=2.3 Hz, 1H), 7.60(dd, J=8.5, 2.1 Hz, 1H), 7.34-7.48 (m, 5H), 6.80 (d, J=8.6 Hz, 1H), 5.01(br. s., 1H), 3.66-4.36 (m, 8H), 3.28-3.64 (m, 8H), 3.12-3.27 (m, 1H),2.05-2.56 (m, 6H), 1.55-1.97 (m, 4H). Following the procedure describedabove for Example 34 and substituting the appropriate reagents, startingmaterials and purification methods known to those skilled in the art,the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 451(3S)-3-[2-Iodo-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]-N,N-dimethylpyrrolidine-1-carboxamide MS m/z (M + H⁺) 632.2 4521-{1-[(3-Iodo-4-{[(3S)-1-(pyrrolidin-1-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 665.2

Example 35

A. Methyl 4-[(3-Chlorophenoxy)methyl]benzoate, 35c

To a mixture of compound 35a (300 mg, 1.31 mmol) and K₂CO₃ (400 mg, 2.88mmol) in DMF (1 mL) was added compound 35b (251 mg, 2.0 mmol). Theresulting mixture was stirred at room temperature for 6 h. The mixturewas poured into water (50 mL) and extracted with EtOAc (3×). Thecombined organic extracts were washed with brine, dried over NaSO₄,filtered, and concentrated under reduced pressure. The resultant residuewas purified by silica gel flash column chromatography, eluting with 20%EtOAc/hexanes to yield compound 35c (340 mg).

B. 4-[(3-Chlorophenoxy)methyl]benzoic acid, 35d

A mixture of compound 35c (340 mg, 1.18 mmol) and LiOH (114 mg, 4.74mmol) in THF/MeOH/H₂O (3/3/3 mL) was stirred for 4 h. A 15% citric acidsolution (10 mL) was added. The mixture was then extracted with EtOAc(3×). The combined organic extracts were washed with brine, dried overNa₂SO₄, and concentrated under reduced pressure. The resultant residue,compound 35d (230 mg) was dried under reduced pressure for 18 h and usedwithout further purification.

C.1-[1-({4-[(3-Chlorophenoxy)methyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 453

A mixture of compound 35d (77 mg, 0.29 mmol), compound 5e (108 mg, 0.38mmol) and HATU (165 mg, 0.44 mmol) in Et₃N (1 mL) and DMF (3 mL) wasstirred for 18 h, and then poured into water (10 mL). The mixture wasthen extracted with EtOAc (3×). The combined organic extracts werewashed with brine (2×), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The resultant residue was purified by flashcolumn chromatography, eluting with 5% MeOH/CH₂Cl₂, to give compound 453(67 mg). MS m/z (M+H⁺) 497.1. ¹H NMR (CD₃OD): δ 7.95 (d, J=2.0 Hz, 1H),7.8 (d, J=2.0 Hz, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H),7.25 (t, J=8.0 Hz, 1H), 7.02 (s, 1H), 6.90-6.98 (m, 2H), 5.15 (s, 2H),4.32-4.45 (m, 2H), 4.15-4.25 (m, 2H), 4.00-4.10 (m, 1H), 3.70-3.82 (br.s, 2H), 2.47 (br. s., 4H).

Following the procedure described above for Example 35 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 454 1-{1-[(4-{[(3-Chlorophenyl)sulfanyl]methyl}phenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 513.1 4553-Chloro-N-[4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)benzyl]aniline MS m/z (M + H⁺) 496.1 5481-[1-({4-[(3- Chlorophenoxy)methyl]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 490.0 959 1-[1-({4-[(3-Chlorophenoxy)methyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 497.0

Example 35a

Following the procedure described above for Example 35 and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Following the procedure described above for Example 35 or Example 1, andsubstituting the appropriate reagents, starting materials andpurification methods known to those skilled in the art, the followingcompounds of the present invention were prepared:

Cpd Cpd Name and Data 551 1-{1-[(4-{[(3-Chlorophenyl)sulfanyl]methyl}phenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 506.0 5493-Chloro-N-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)benzyl]aniline MS m/z (M + H⁺) 489.0 9561-{1-[(4-{[(3- Chlorophenyl)sulfanyl]methyl}phenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl) piperazine MS m/z (M + H⁺) 513.0 9693-Chloro-N-[4-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)benzyl]aniline MS m/z(M + H⁺) 496.0

Example 35b

Following the procedure described above for Example 1c, and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Salt Cpd Cpd Name and Data Form 955 1-{1-[(4-{[(3- N-TFAChlorophenyl)sulfanyl]methyl}phenyl)carbonyl]azetidin-3-yl}-4-(trifluoroacetyl)piperazine MS m/z (M + H⁺) 498.0 9643-Chloro-N-[4-({3-[4-(trifluoroacetyl)piperazin-1- N-TFAyl]azetidin-1-yl}carbonyl)benzyl]aniline MS m/z (M + H⁺) 481.0

Example 36

1-(Phenylcarbonyl)-4-{1-[(2-pyrrolidin-3-ylphenyl)carbonyl]azetidin-3-yl}piperazine,Cpd 456

To a solution of compound III (300 mg, 0.58 mmol) in 1,4-dioxane (10 mL)was added 6N HCl (3 mL). After stirring for 4 h, the solvent wasevaporated in vacuo. The residue was partitioned between EtOAc and 3NNaOH, and the organic phase was isolated and dried over MgSO₄. Themixture was filtered, the filtrate concentrated under reduced pressure,and the residue was purified by reverse phase HPLC to give compound 456(52.3 mg). LC/MS m/z (M+H⁺) 419.36 (calculated for C₂₅H₃₀N₄O₄, 418.54).

Example 37

A. tert-Butyl4-[1-(diphenylmethyl)azetidin-3-yl]-3-(hydroxymethyl)piperazine-1-carboxylate,37b

Compound 37a (811 mg, 3.21 mmol) was added in one portion to a stirringsuspension of anhydrous K₂CO₃ (1.07 g, 7.9 mmol) in MeOH (4 mL). Themixture was stiffed for 1.5 h at room temperature, and the MeOH was thenremoved under reduced pressure to near-dryness. The resulting whiteslurry was triturated with CH₂Cl₂ (40 mL) and filtered through amedium-porosity glass fitted funnel. The solids were washed withadditional CH₂Cl₂ and the combined filtrates were concentrated and driedunder reduced pressure to give compound 37a (733 mg) as a white solid,the free base of the HCl salt of 37a.

The material was suspended in CH₃CN (8 mL) with compound 1e (1.07 g,3.37 mmol). Diisopropylethylamine (1.23 mL, 7.06 mmol) was added and themixture was heated at 60° C. for 14 h. EtOAc (100 mL) was added and theorganic phase was washed with water (20 mL) and brine (20 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure to give acrude residue (1.42 g) as a pale orange foam. The material was purifiedby medium pressure liquid chromatography (MPLC) using an ISCO CombiFlashsystem (silica gel, 10-50% EtOAc/hexanes) to give compound 37b (979 mg)as a white foam. ¹H NMR (400 MHz, CDCl₃): δ 7.39 (d, J=8.1 Hz, 4H),7.23-7.33 (m, 4H), 7.14-7.23 (m, 2H), 4.34 (s, 1H), 3.28-3.58 (m, 8H),2.76-2.95 (m, 2H), 2.26-2.75 (m, 4H), 2.20 (dt, J=12.3, 4.9 Hz, 1H),1.44 (s, 9H); LCMS m/z (M+H⁺) 438.5, (M+Na⁺) 460.5.

B. {1-[1-(Diphenylmethyl)azetidin-3-yl]-piperazin-2-yl}methanol, 37c

Compound 37b (450 mg, 1.03 mmol) was dissolved in CH₂Cl₂ (6 mL) and TFA(3 mL) and was stirred at 20° C. for 2.5 h. The reaction mixture wasconcentrated to dryness under reduced pressure to give the TFA salt ofcompound 37c as an orange foam. Compound 37c was used in the followingstep without further purification. MS m/z (M+H⁺) 338.2.

C.{1-[1-(Diphenylmethyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazin-2-yl}methanol,37e

Compound 37c (1.03 mmol) was dissolved in CH₂Cl₂ (5 mL) and cooled in anice water bath to 0° C. A 10% aqueous Na₂CO₃ solution (5 mL) was addedand a solution of compound 37d (143 μL, 1.23 mmol) dissolved in CH₂Cl₂(1 mL) was added dropwise. The resultant mixture was allowed to warm to20° C. and then stirred rapidly for 62 h. CH₂Cl₂ (10 mL) was added tothe reaction mixture and the aqueous phase was extracted with CH₂Cl₂(2×20 mL). The combined organic extracts were washed with brine, driedover Na₂SO₄, filtered, and concentrated to give compound 37e (465 mg) asan off white foam. Compound 37e was used in the following step withoutfurther purification. ¹H NMR (400 MHz, CDCl₃): δ 7.39 (m, 9H), 7.22-7.32(m, 4H), 7.14-7.23 (m, 2H), 4.35 (s, 1H), 4.07 (br. s, 1H), 3.30-3.71(complex, 8H), 2.2-3.0 (complex, 6H); LCMS m/z (M+H⁺) 442.2.

D. [1-Azetidin-3-yl-4-(phenylcarbonyl)piperazin-2-yl]methanol, 37f

Compound 37e (450 mg, 1.02 mmol) was added to a 500 mL-Parrhydrogenation bottle and dissolved in absolute EtOH (6 mL). A 12N conc.HCl solution (95 μL, 1.14 mmol) was added and the bottle was purged withN₂. 10% Pd/C (264 mg) was added and the mixture was shaken under 60 psiof H₂ for 14 h. An additional amount of 10% Pd/C (430 mg) was added andthe mixture was returned to 60 psi of H₂ and shaken 5 h more. Themixture was filtered through a pad of diatomaceous earth, and the solidswere rinsed thoroughly with MeOH. The fitrate was concentrated todryness under reduced pressure to afford crude compound 37f as a stickyoil (428 mg) which was used in the following step without furtherpurification. LC/MS m/z (M+H⁺) 276.3.

E.[1-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazin-2-yl]ethanol,Cpd 457

Compound 3a (142 mg, 0.67 mmol) and HATU (256 mg, 0.67 mmol) weresuspended in CH₂Cl₂ (1 mL) and DMF (0.2 mL). Et₃N (195 μL, 1.4 mmol) wasadded and the solution was stiffed for 15 min at 20° C. Crude compound37f (214 mg, approximately 0.56 mmol) was dissolved in 1:1 CH₂Cl₂/DMF (3mL) and was added in portions to the solution of compound 3a and themixture was stirred for 64 h. The organic solution was diluted withEtOAc (50 mL), and washed sequentially with water (3×10 mL), and brine(10 mL). The organic phase was dried over Na₂SO₄, filtered, and thefiltrate concentrated under reduced pressure to give a yellow oil (310mg). The crude oil was purified by MPLC (4g Silicycle SiO₂ cartridge,15-80% acetone/hexanes) to give compound 457 as a white foam (104 mg).¹H NMR (400 MHz, CDCl₃) δ: 7.53 (d, J=7.8 Hz, 2H), 7.42 (br. s, 5H),7.11-7.37 (m, 7H), 4.26 (m, 5H), 4.00 (s, 2H), 3.71-3.89 (m, 1H),3.54-3.71 (m, 3H), 3.25-3.54 (m, 3H), 2.92 (br. s., 1H), 2.64 (br. s.,1H), 2.41 (br. s., 1H); LCMS m/z (M+H⁺) 470.5.

Following the procedure described above for Example 37 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 458 {1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazin-2-yl}methanol ¹H NMR (400 MHz, CDCl₃): δ7.65-7.73 (m, 2H), 7.61 (dd, J = 11.6, 8.1 Hz, 4H), 7.33-7.50 (m, 10H),3.96-4.49 (m, 5H), 3.76-3.91 (m, 1H), 3.63 (m, 3H), 3.32-3.53 (m, 1H),2.95 (br. s., 1H), 2.64 (br. s., 1H), 2.45 (br. s., 1H) LCMS m/z (M +H⁺) 456.5 459 [4-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-1-(phenylcarbonyl)piperazin-2-yl]methanol ¹H NMR (400 MHz, CDCl₃): δ 7.55(d, J = 8.1 Hz, 2H), 7.35-7.46 (m, 5H), 7.10-7.34 (m, 7H), 4.82 (br. s.,1H), 4.01 (s, 2H), 3.72-4.40 (m, 5H), 3.52 (br. s., 1H), 3.16 (br. s.,1H), 2.54-3.04 (m, 2H), 1.93-2.30 (m, 4H) LCMS m/z (M + H⁺) 470.5 460{4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-1-(phenylcarbonyl)piperazin-2-yl}methanol ¹H NMR (400 MHz, CDCl₃): δ7.67-7.75 (d, J = 8.3 Hz, 2H), 7.55-7.67 (m, 4H), 7.34-7.52 (m, 8H),3.39-4.96 (m, 9H), 3.20 (quin, 1H), 2.51-3.05 (m, 3H), 2.22 (br. s.,1H), 2.04 (br. s., 1H) LCMS m/z (M + H⁺) 456.5

Example 38

4,4,4-Trifluoro-N-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]butanamide,Cpd 497

A mixture of Cpd 495 (65 mg, prepared according to Example 9),4,4,4-trifluorobutanoic acid (30 mg), HATU (116 mg), and TEA (0.12 mL)in DCM 1.5 mL) was stirred at room temperature for 5 hr. The reactionmixture was diluted with DCM and water. The normal work-up followed bychromatography gave Cpd 497 (71 mg). MS m/z (M+H⁺) 489.5.

Following the procedure described above for Example 38 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 4982-Phenyl-N-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]acetamide MS m/z (M + H⁺) 483.6 499N-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]cyclohexanecarboxamide MS m/z (M + H⁺) 475.6 5002-Ethyl-N-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]butanamide MS m/z (M + H⁺) 463.6⁺ 501N-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]benzamide MSm/z (M + H⁺) 469.2

Example 39

A.N-(Naphthalen-2-ylmethyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline,Cpd 495

Cpd 496 was dissolved in CH₂Cl₂ and TFA and was stiffed at 20° C. Thereaction mixture was concentrated to dryness under reduced pressure togive Cpd 495, which was used in the following step without furtherpurification. MS m/z (M+H⁺) 365.

B.N-(Naphthalen-2-ylmethyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline,Cpd 491

A mixture of Cpd 495 (100 mg, 0.27 mmol), compound 39a (75 mg, 0.48mmol) and AcOH (0.5 mL) in 1,2 dichloroethane (3 mL) was stirred for 1h, then NaBH(OAc)₃ (136 mg, 0.64 mmol) was added. The resulting mixturewas stirred overnight, then was poured into 2N aqueous KOH solution (20mL) and extracted with EtOAc. The combined extracts were dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby flash column chromatography, eluting with 5% MeOH/CH₂Cl₂ to give 33.2mg of Cpd 491. ¹H NMR (400 MHz, CDCl₃): δ 7.75-7.85 (m, 4H), 7.43-7.53(m, 5H), 7.35-7.42 (m, 5H), 6.61 (d, J=8.8 Hz, 2H), 4.64 (br. s., 1H),4.51 (s, 2H), 4.27 (br. s., 1H), 4.08-4.35 (m, 3H), 4.02 (s, 1H), 3.89(s, 1H), 3.71 (br. s., 1H), 3.34-3.55 (m, 2H), 3.10-3.22 (m, 1H),2.13-2.49 (m, 3H); MS m/z (M+H⁺) 505.3.

Following the procedure described above for Example 39 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 492N-(2-Chlorobenzyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline MS (m/z) (M + H⁺) 489.2 493N-(3,4-Dichlorobenzyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline MS (m/z) (M + H⁺) 523.2 494N-[4-Fluoro-3-(trifluoromethyl)benzyl]-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline MS (m/z)(M + H⁺) 541.2

Example 40

1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[(1RS,2RS)-2-{4-[(trifluoromethyl)sulfanyl]phenyl}cyclopropyl]carbonyl}azetidin-3-yl)piperazine,Cpd 645 (racemic, trans)

Trimethylsulfoxonium iodide 40a (1.15 mmol, 253 mg) and sodium hydride(60% dispersion in mineral oil, 1.1 mmol, 44 mg) were combined in 3 mLof dry DMSO and stirred 20 min at room temperature. Cpd 648, prepared inExample 5, was added and the mixture was stirred 15 min at roomtemperature, then heated at 50° C. overnight. After cooling, the mixturewas partitioned between EtOAc and water, The organic layer was separatedand concentrated to give crude product that was purified by preparativereverse-phase chromatography to afford 9.1 mg (2%) of Cpd 645 as themono-TFA salt. MS m/z (M+H⁺) 497.2.

Following the procedure described above for Example 40, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compound of the presentinvention was prepared:

Cpd Cpd Name and Data 642 1-(1-{[(1RS,2RS)-2-(2-Chlorophenyl)cyclopropyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 431.1

Example 41

Intentionally left blank.

Example 42

A. Methyl 4-(4-(trifluoromethyl)benzyl)benzoate, 42b

Argon was bubbled through a mixture of methyl 4-bromobenzoate 42a (9.3mmol, 2.0 g), 2 mL of THF, and 4-trifluoromethylbenzylzinc chloride (0.5M in THF, 46.5 mmol, 93 mL) for 5 min Pd(dffp)Cl₂.CH₂Cl₂(0.5 mol, 409mg) was added and the reaction tube was capped and heated at 70° C. for16 h. The mixture was cooled and filtered through Celite. Water wasadded to the filtrate and the resulting solid was filtered off. Theorganic solution was dried over MgSO₄ and concentrated. The crudeproduct was purified by flash chromatography (silica gel, 0-10% EtOAc inheptane) to give 1.5 g (55%) of methyl4-(4-(trifluoromethyl)benzyl)benzoate, 42b.

B. 4-(4-(Trifluoromethyl)benzyl)benzoic acid, 42c

Following the procedure described in Example 91, Step P, methyl4-(4-(trifluoromethyl)benzyl)benzoate 42b (1.5 g, 5.1 mmol) wasconverted to methyl 1.31 g (92%) of 4-(4-(trifluoromethyl)benzyl)benzoicacid, 42c. MS m/z (M+H⁺) 279.1.

Following the procedure described above for Example 42 and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Intermediate compounds were optionally prepared by an alternativeprocedure:

C. Methyl 4-(4-(trifluoromethyl)benzyl)benzoate, 42b

A mixture of 4-bromomethyl-benzoic acid methyl ester 42d (1.0 g, 4.37mmol), 4-trifluorophenyl boronic acid 42e (0.995 g, 5.24 mmol), andPd(PPh₃)₄ (50 mg, 0.044 mmol) in dioxane (15 mL) was stirred at roomtemperature for 1 min. Next, 4 mL of 2 M aqueous Na₂CO₃ solution wasadded. The resulting solution was heated at 90° C. for 5 h and was thencooled to rt. EtOAc and water were added to the reaction mixture. Theorganics were concentrated and purified by flash chromatography (silicagel, 5% EtOAc/hexanes) to give methyl4-(4-(trifluoromethyl)benzyl)benzoate, 42b.

Following the procedure described above for Example 2 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 961-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]-4-({4-[4-(trifluoromethyl)benzyl]phenyl}carbonyl)piperazine ¹H NMR (400 MHz,CDCl₃): δ 9.23 (s, 1H); 8.44 (s, 1H); 8.0-7.8 (m, 2H); 7.76-7.63 (m,2H); 7.5 (d, 1H); 7.44-7.32 (m, 3H); 4.9-4.7 (m, 3H); 4.3-4.2 (m, 2H);4.19-4.04 (m, 3H) MS m/z (M + H⁺) 515.1 971-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]-4-({4-[4-(trifluoromethyl)benzyl]phenyl}carbonyl)piperazine ¹H NMR (400 MHz,CDCl₃): δ 8.12 (m, 2H); 7.68 (m, 2H); 7.5 (m, 2H); 7.4 (m, 4H); 4.85(bs, 2H); 4.47-4.26 (bm, 3H); 3.52 (bs, 4H); 3.02 (bs, 2H). MS m/z (M +H⁺) 495.1 006 1-({4-Fluoro-3-[4-(trifluoromethyl)benzyl]phenyl}carbonyl)-4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 533.1 0161-({2-Methyl-3-[4-(trifluoromethyl)benzyl]phenyl}carbonyl)-4-[1-(1,3-thiazol-5-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 529.2

Following the procedure described above for Example 9 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 563 1-[1-({4-Fluoro-3-[4-(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 526.1 10071-[1-({4-Fluoro-3-[4-(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (400 MHz, CDCl₃): δ 7.89(s, 1H); 7.78 (s, 1H); 7.50 (m, 5H); 7.82 (m, 2H); 7.12 (t, 1H); 4.69(bm, 2H); 4.48 (bm, 2H); 4.32 (bm, 2H); 4.0 (s, bm, 5H); 3.5 (bm, s 2H)MS m/z (M + H⁺) 533.1 1008 1-[1-({2-Methyl-3-[4-(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 529.2 10091-[1-({2-Methyl-3-[4-(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 529.2 10131-[1-({2-Methyl-3-[4-(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]-4-(1H-pyrrol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 511.2 10141-(Isothiazol-5-ylcarbonyl)-4-[1-({2-methyl-3-[4-(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z(M + H⁺) 529.2 1015 1-[1-({2-Methyl-3-[4-(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-5-ylcarbonyl)piperazine MS m/z (M + H⁺) 529.2 9951-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[3-(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z515 (M + H⁺) 985 1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[4-(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z(M + H⁺) 515 998 1-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({4-[3-(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z(M + H⁺) 515 999 1-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({4-[4-(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z(M + H⁺) 515 771 1-(Phenylcarbonyl)-4-[1-({4-[4-(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z(M + H⁺) 508 547 1-(Phenylcarbonyl)-4-[1-({4-[3-(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z(M + H⁺) 508

Example 43

A. Methyl 3-(4-fluorobenzoyl)-1H-indole-6-carboxylate, 43c

A solution of 4-fluorobenzoyl chloride 43b (2 mmol, 0.24 mL) in 8 mL ofDCE was added dropwise to an ice-cold solution of methyl1H-indole-6-carboxylate 43a (1.43 mmol, 250 mg) and diethylaluminumchloride (1 M in hexanes, 1.86 mmol, 1.86 mL) in 8 mL of DCE. After 2 hat 0° C., the mixture was warmed to room temperature and was stirredovernight. To the mixture was added pH 7 buffer; the resulting solid wasfiltered and washed with CH₂Cl₂ to give 162 mg (38%) of methyl3-(4-fluorobenzoyl)-1H-indole-6-carboxylate 43c. MS m/z (M+H⁺) 298.0.

B. 3-(4-Fluorobenzoyl)-1H-indole-6-carboxylic acid, 43d

Following the procedure described in Example 91, Step P, 110 mg (72%) of3-(4-fluorobenzoyl)-1H-indole-6-carboxylic acid was obtained.

Following the procedure described above for Example 43 and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Following the procedure described above for Example 9 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 1025 (4-Fluorophenyl)[6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-3-yl]methanone MS m/z (M + H⁺) 518.2 802((4,4-Difluorocyclohexyl)[6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-3-yl]methanone MS m/z (M + H⁺) 542.1 949(6-Chloropyridin-3-yl)[6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-3-yl]methanone MS m/z (M + H⁺) 535.0 950Pyridin-3-yl[6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-3-yl]methanone MS m/z (M + H⁺)501.0

Example 44

A. Methyl 4-(pyridin-2-yloxy)-benzoate, 44b

A mixture of 29a (433 mg, 2.85 mmol), 44a (300 mg, 1.90 mmol),Cu(biPy)₂BF₄ (88 mg, 0.19 mmol), K₃PO₄ (805 mg, 3.80 mmol), and DMF (1.5mL) was heated at 140° C. for 1 h. After 0.5 h, the mixture was pouredinto water (60 mL) and extracted with EtOAc. The combined extracts werewashed with brine, dried over Na₂SO₄ and concentrated. The crude productwas purified by flash column chromatography (silica gel, 20%EtOAc/hexanes) to give 298 mg of 44b.

B. 4-(Pyridin-2-yloxy)-benzoic acid, 44c

A mixture of 44b (430 mg, 1.87 mmol), LiOH (180 mg, 7.5 mmol), THF (3mL), MeOH (3 mL), and H₂O (3 mL) was stirred at room temperature for 4h. Then the reaction mixture was acidified with 15% citric acid (10 mL).The mixture was extracted with EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄, and concentrated to give 44c (350 mg).

C.1-(1-{[4-(Pyridin-2-yloxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 913

A mixture of 44c (60 mg, 0.28 mmol), 5e (105 mg, 0.36 mmol), HATU (159mg, 0.42 mmol), Et₃N (1 mL), and DMF (3 mL) was stirred at roomtemperature overnight, and then poured into water (10 mL). The mixturewas extracted with EtOAc. The extracts were washed with brine, driedover Na₂SO₄ and concentrated. The residue was purified by flash columnchromatography (silica gel, 7% MeOH/CH₂Cl₂) to give 98 mg of Cpd 913. MSm/z (M+H⁺) 450.0.

Following the procedure described above for Example 44, Steps A and B,and substituting the appropriate reagents, starting materials andpurification methods known to those skilled in the art, the followingintermediate compounds were prepared.

Following the procedure described above for Example 44, Step C, andsubstituting the appropriate reagents, starting materials andpurification methods known to those skilled in the art, the followingcompounds of the present invention were prepared.

Cpd Cpd Name and Data 527 1-(Phenylcarbonyl)-4-(1-{[4-(pyridin-3-yloxy)phenyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 443.0 5071-{1-[(4-{[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MSm/z (M + H⁺) 545.0 533 1-[1-({4-[(5-Methoxypyridin-3-yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MSm/z (M + H⁺) 497.0 1484 1-(Phenylcarbonyl)-4-(1-{[4-(pyridin-2-yloxy)phenyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 443.0 8751-(1-{[4-(3-Chlorophenoxy)-3-fluorophenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 500.8 6631-{1-[(4-{[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 551.8 7341-(1-{[4-(Pyridin-3-yloxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 450.0 9041-[1-({4-[(5-Methoxypyridin-3-yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 480.0 5321-[1-({4-[(5-Bromopyridin-2- yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 522.8 5371-(1-{[3-Fluoro-4-(pyridin-2- yloxy)phenyl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 461.0 5201-[1-({4-[(5-Chloropyridin-2- yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 477.0 5251-(1-{[3-Chloro-4-(pyridin-2- yloxy)phenyl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 477.0 5221-[1-({4-[(6-Fluoropyridin-2- yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 504.0 5181-(Phenylcarbonyl)-4-{1-[(4-{[4-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 511.0877 1-[1-({4-[(5-Bromopyridin-2-yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 529.8 7651-[1-({4-[(5-Bromopyridin-2-yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 529.8 9091-(1-{[3-Fluoro-4-(pyridin-2-yloxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 468.0 7171-[1-({4-[(5-Chloropyridin-2-yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 484.0 7521-(1-{[3-Chloro-4-(pyridin-2-yloxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 484.0 7151-[1-({4-[(6-Fluoropyridin-2-yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 468.0 6521-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{[4- (trifluoromethyl)pyridin-2-yl]oxy}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 518.0

Example 44a

Following the procedure described above for Example 1c, and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data Salt Form 837 1-(Trifluoroacetyl)-4-{1-[(4-{[4-N-TFA (trifluoromethyl)pyridin-2- yl]oxy}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 503.0 869 1-(1-{[4-(Pyridin-2- N-TFAyloxy)phenyl]carbonyl}azetidin-3-yl)-4- (trifluoroacetyl)piperazine MSm/z (M + H⁺) 435.0 872 1-[1-({4-[(5-Bromopyridin-2- N-TFAyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4- (trifluoroacetyl)piperazine MSm/z (M + H⁺) 512.8 802 1-{1-[(4-{[3-Chloro-5- N-TFA(trifluoromethyl)pyridin-2- yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-(trifluoroacetyl)piperazine MS m/z (M + H⁺) 536.8

Example 44b

Following the procedure described above for Example 1, and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared.

Cpd Cpd Name and Data 9221-(1-{[4-(Pyridin-2-yloxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 450.0 7571-[1-({4-[(5-Chloropyridin-2-yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 484.0 7841-[1-({4-[(6-Fluoropyridin-2-yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 468.0 7691-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(4-{[4-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 518.0 7201-{1-[(4-{[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 551.8

Example 45

A. Methyl 6-(3-chloro-phenoxy)-nicotinate, 5c

A mixture of 45a (200 mg, 0.926 mmol), 45b (178 mg, 1.39 mmol),Cu(biPy)₂BF₄ (43 mg, 0.09 mmol), K₃PO₄ (392 mg, 1.85 mmol), and DMF (1.0mL) was heated at 140° C. for 1 h. The reaction mixture was then pouredinto water (30 mL) and extracted with EtOAc. The extracts were washedwith brine, dried over Na₂SO₄, and concentrated. The crude product waspurified by flash column chromatography (silica gel, 20% EtOAc/hexanes)to give 202 mg of 45c.

B. 6-(3-Chloro-phenoxy)-nicotinic acid, 5d

A mixture of 45c (202 mg, 0.766 mmol), LiOH (74 mg, 3.06 mmol), THF (2mL), MeOH (2 mL) and H₂O (2 mL) was stirred at room temperature for 4 h.The reaction mixture was acidified with 15% citric acid (10 mL) andextracted with EtOAc. The extracts were washed with brine, dried overNa₂SO₄, and concentrated to give 177 mg of 45d.

C.1-(1-{[6-(3-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine,Cpd 519

A mixture of 45d (60 mg, 0.24 mmol), 2c (101 mg, 0.36 mmol), HATU (137mg, 0.36 mmol), Et₃N (0.5 mL), and DMF (3 mL) was stirred at roomtemperature overnight. The mixture was poured into water (30 mL) andextracted with EtOAc. The extracts were washed with brine, dried overNa₂SO₄, and concentrated. The residue was purified by flash columnchromatography (silica gel, 5% MeOH/CH₂Cl₂) to give 50 mg of Cpd 519. ¹HNMR (CDCl₃): δ 8.35-8.49 (m, 1H), 8.06 (dd, J=8.5, 2.1 Hz, 1H),7.32-7.49 (m, 6H), 7.14-7.27 (m, 2H), 6.94-7.11 (m, 2H), 4.24 (br. s.,1H), 4.15 (br. s., 2H), 4.00-4.14 (m, 2H), 3.65-3.94 (m, 2H), 3.37-3.60(m, 2H), 3.16-3.33 (m, 1H), 2.44 (br. s., 4H). MS m/z (M+H⁺) 477.0.

Following the procedure described above for Example 45, Steps A and B,and substituting the appropriate reagents, starting materials andpurification methods known to those skilled in the art, the followingintermediate compounds were prepared.

Following the procedure described above for Example 45, Step C, andsubstituting the appropriate reagents, starting materials andpurification methods known to those skilled in the art, the followingcompounds of the present invention were prepared.

Cpd Cpd Name and Data 514 1-(Phenylcarbonyl)-4-[1-({6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}carbonyl)azetidin-3- yl]piperazineMS m/z (M + H⁺) 511.0 5211-(1-{[6-(2-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 477.0 6831-(1-{[6-(3-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 484.0 6601-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}carbonyl)azetidin-3- yl]piperazineMS m/z (M + H⁺) 518.0 7081-(1-{[6-(2-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 484.0 8781-[1-({6-[2-Fluoro-5-(trifluoromethyl)phenoxy]pyridin-3-yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 536.0

Example 45a

Following the procedure described above for Example 1, and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared.

Cpd Cpd Name and Data 8031-(1-{[6-(3-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 504.0 6891-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}carbonyl)azetidin-3- yl]piperazineMS m/z (M + H⁺) 518.0 8111-(1-{[6-(2-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 484.0

Example 46

A. 1-(4-Chloro-phenyl)-2-methyl-pent-1-en-3-one, 46b

To 4-chlorobenzaldehyde 46a (99.6 mmol, 14g) in water (44 mL) was addedKOH (44.6 mmol, 2.5 g). The mixture was heated at 65° C. and 3-pentanone(99.6 mmol, 8.58 g) was added dropwise over 10 min. After refluxing for8 h, the reaction mixture was cooled to room temperature and stirredovernight. Following addition of 260 mL 1N aqueous HCl, the mixture wasextracted with EtOAc. The organic layer was dried over Na₂SO₄ andconcentrated. The crude product was purified by flash columnchromatography (silica gel, 5% EtOAc/heptane) to give 8.59 g of 46b.

B. Ethyl 6-(4-chloro-phenyl)-3,5-dimethyl-2,4-dioxo-hex-5-enoate, 46c

To a solution of LiHMDS ON solution in THF, 5.48 mmol, 5.17 mL) in THF(16 mL) at −78° C. was added a solution of 46b (4.98 mmol, 1.04 g) inTHF (2.5 mL) drop wise. After stirring at −78° C. for 1 h, the mixturewas treated with a solution of diethyl oxalate (4.98 mmol, 0.73 g) inTHF (2.5 mL). After stirring at −78° C. for 1 h, then the mixture waswarmed up to room temperature and stiffed overnight. The solvent wasevaporated and the crude product was taken up in EtOAc, and washed with1N HCl and brine. The organic layer was dried over Na₂SO₄ andconcentrated to give 1.5 g of 46c.

C.5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylate,46e

A mixture of 46c (15.6 mmol, 4.82 g), 2,4-dichlorophenylhydrazine 46d(17.2 mmol, 3.67 g), K₂CO₃ (17.2 mmol, 2.37 g) and EtOH (137 mL) wasstirred at 70° C. overnight. The solid was filtered off and washed withEtOH. The filtrates were concentrated and purified by flash columnchromatography (silica gel, 5% EtOAc/heptane) to give 2.25 g of 46e.

D.5-[2-(4-Chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid, 46f

The mixture of 46e (3.34 mmol, 1.5 g), LiOH (13.3 mmol, 319 mg), THF (7mL), MeOH (7 mL), and H₂O (37 mL) was stirred at room temperature for 4h. The mixture was acidified with 1N HCl to pH=5 and extracted withEtOAc. The organic layer was dried over Na₂SO₄ and concentrated to give46f (202 mg).

E.5-[2-(4-Chlorophenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid, Cpd 1010

To a solution of 46f (0.138 mmol, 60 mg) in CH₂Cl₂ and THF was addedSOCl₂ (2 N solution in THF, 0.414 mmol, 0.212 mL). After refluxing for 4h, the mixture was concentrated and dried under vacuum for 1 h. Inanother flask was added 5e (0.18 mmol, 52 mg), CH₂Cl₂ (3 mL), and DIPEA(0.69 mmol, 0.12 mL). To this solution was added the crude product fromthe SOCl₂ reaction dissolved in CH₂Cl₂ (1 mL). After stirring at roomtemperature for 1 h, the mixture was diluted with CH₂Cl₂ (15 mL), washedwith 3N NaOH aqueous solution (30 mL) and brine (30 mL), dried overNa₂SO₄, and concentrated. The crude product was purified by flash columnchromatography (silica gel, 4% MeOH/CH₂Cl₂) to give 74 mg of Cpd 1010.¹H NMR (CDCl₃): δ 7.87 (d, J=3.5 Hz, 1H), 7.55 (t, J=2.3 Hz, 2H),7.33-7.36 (m, 2H), 7.30 (d, J=8.6 Hz, 2H), 7.13 (d, J=8.6 Hz, 2H), 6.41(s, 1H), 4.49-4.62 (m, 2H), 4.41 (dd, J=10.4, 5.3 Hz, 2H), 4.22 (dd,J=10.0, 7.2 Hz, 1H), 4.04-4.10 (m, 1H), 3.87 (br. s., 1H), 3.82 (br. s.,1H), 3.18-3.26 (m, 1H), 2.41-2.58 (m, 4H), 2.39 (s, 3H), 1.88 (s, 3H).MS m/z (M+H⁺) 657.0.

Following the procedure described above for Example 46, Steps A-D orB-D, and substituting the appropriate reagents, starting materials andpurification methods known to those skilled in the art, the followingintermediate compounds were prepared.

Following the procedure described above for Example 46, Step E, orExample 1, and substituting the appropriate reagents, starting materialsand purification methods known to those skilled in the art, thefollowing compounds of the present invention were prepared.

Cpd Cpd Name and Data 10111-[1-({5-[(E)-2-(4-Chlorophenyl)-1-methylethenyl]-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl}carbonyl)azetidin-3-yl]-4-(1H-pyrrol-2- ylcarbonyl)piperazine MS m/z(M + H⁺) 639.2 1018 (7E)-7-[(4-Chlorophenyl)methylidene]-1-(2,4-dichlorophenyl)-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7-tetrahydro-1H-indazole MS m/z (M + H⁺) 669.0 1019(7E)-7-[(4-Chlorophenyl)methylidene]-1-(2,4-dichlorophenyl)-3-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7-tetrahydro-1H-indazole MS m/z (M + H⁺) 651.2 1021(7Z)-1-(2,4-Dichlorophenyl)-7-[(4-fluorophenyl)methylidene]-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,4,6,7-tetrahydrothiino[4,3-c]pyrazole MS m/z (M + H⁺) 671.0 1024(7Z)-1-(2,4-Dichlorophenyl)-7-[(4-fluorophenyl)methylidene]-3-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,4,6,7-tetrahydrothiino[4,3-c]pyrazole MS m/z (M + H⁺) 651.2 12671-(2,4-Dichlorophenyl)-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7-tetrahydro-1H-indazole MS m/z (M + H⁺) 645.2 13091-(2,4-Dichlorophenyl)-3-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7-tetrahydro-1H-indazole MS m/z (M + H⁺) 627.2 1023(7E)-7-[(4-Chlorophenyl)methylidene]-1-(2,4-dichlorophenyl)-3-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7-tetrahydro-1H-indazole MS m/z (M + H⁺) 669.1 13041-(2,4-Dichlorophenyl)-3-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7-tetrahydro-1H-indazole MS m/z (M + H⁺) 545.2

Example 46a

Following the procedure described above for Example 1c, and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data Salt Form 1012 1-[1-({5-[(E)-2-(4-Chlorophenyl)-1-N-TFA methylethenyl]-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl}carbonyl)azetidin-3-yl]-4- (trifluoroacetyl)piperazineMS m/z (M + H⁺) 642.9 1020 (7E)-7-[(4-Chlorophenyl)methylidene]-1-(2,4-N-TFA dichlorophenyl)-3-({3-[4-(trifluoroacetyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7-tetrahydro-1H-indazole MS m/z (M + H⁺) 654.0 1022(7Z)-1-(2,4-Dichlorophenyl)-7-[(4- N-TFAfluorophenyl)methylidene]-3-({3-[4-(trifluoroacetyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,4,6,7-tetrahydrothiino[4,3- c]pyrazole MS m/z (M + H⁺)654.1 1311 1-(2,4-Dichlorophenyl)-3-({3-[4- N-TFA(trifluoroacetyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7-tetrahydro-1H-indazole MS m/z (M + H⁺) 530.2

Example 47

4-(((2-fluorophenyl)amino)methyl)benzoic acid, 47c

A mixture of 4-formylbenzoic acid 47a (3.33 mmol, 500 mg),2-fluoroaniline 47b (3.33 mmol, 370 mg), and decaborane (1 mmol, 122 mg)in 8 mL of MeOH was stirred at room temperature for 15 min. The mixturewas concentrated and purified by preparative reverse-phasechromatography to afford 0.81 g (99%) of 47c.

Following the procedure described above for Example 47, and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared.

Following the procedure described above for Example 1 or Example 9, andsubstituting the appropriate reagents, starting materials andpurification methods known to those skilled in the art, the followingcompounds of the present invention were prepared.

Cpd Cpd Name and Data 5532-Fluoro-N-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)benzyl]aniline MS m/z (M + H⁺) 473.1 529N-Benzyl-2-chloro-5-methoxy-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)aniline MS m/z(M + H⁺) 520.2 530 N-(4,4-Difluorocyclohexyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)aniline MS m/z(M + H⁺) 483.2 561 2-Fluoro-N-[3-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)benzyl]aniline MS m/z (M + H⁺) 473.1 5562,6-Difluoro-N-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)benzyl]aniline MS m/z (M + H⁺) 491.0 542N-Benzyl-2-iodo-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline MS m/z (M + H⁺) 581.0 5572,3,4-Trifluoro-N-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)benzyl]aniline MS m/z (M + H⁺) 509.2 10052-Fluoro-N-[3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)benzyl]aniline MS m/z (M + H⁺) 480.3

Example 48

4-(Cyclohexanecarboxamido)benzoic acid, 48d

A mixture of 4-aminobenzoic acid 48a (1.98 mmol, 300 mg),cyclohexanecarbonyl chloride 48b (1.98 mmol, 291 mg), and Et₃N (2.52mmol, 0.43 mL) in 6 mL of THF was stirred at room temperature overnight.1N aqueous NaOH (7.9 mmol, 7.9 mL) was added to the mixture (containingmethyl 4-(cyclohexanecarboxamido)benzoate 48c) and the reaction mixturewas stirred for 5 h at room temperature. The THF was removed by rotaryevaporation and 1N aqueous HCl was added to precipitate the product,which was filtered to give 480 mg (92%) of 48d.

Following the procedure described above for Example 9, and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compound of the presentinvention was prepared.

Cpd Cpd Name and Data 709N-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]cyclohexanecarboxamide MS m/z (M + H⁺)482.1

Example 49

2-(4,4-Difluoropiperidin-1-yl)benzo[d]thiazole-6-carboxylic acid, 49d

A mixture of ethyl 2-bromo-benzo[d]thiazole-6-carboxylate 49a (1.75mmol, 500 mg), 4,4-difluoropiperidine 49b (1.92 mmol, 303 mg), andCs₂CO₃ (5.24 mmol, 1.71 g) in 15 mL of CH₃CN was refluxed overnight. Thesuspension was cooled to room temperature and 15 mL of water was addedto the mixture (containing ethyl2-(4,4-difluoropiperidin-1-yl)benzo[d]thiazole-6-carboxylate 49c). Thereaction mixture was heated at 60° C. for 18 h. After cooling, themixture was acidified using 3N aqueous HCl and the resulting precipitatewas filtered to give 575 mg (99%) of 49d. MS m/z (M+H⁺) 299.1.

Following the procedure described above for Example 9, and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compound of the presentinvention was prepared.

Cpd Cpd Name and Data 6712-(4,4-Difluoropiperidin-1-yl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzothiazole MSm/z (M + H⁺) 533.2

Example 50

3-Chloro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole,Cpd 1365

To a solution of Cpd 487 (0.2 mmol, 100 mg) in CCl₄ (4 mL) and CH₂Cl₂ (4mL) was added NCS (0.25 mmol, 33 mg). The reaction mixture was stirredat room temperature for 4 h. It was then diluted with CH₂Cl₂ and washedwith 1N aqueous NaOH and H₂O, dried over Na₂SO₄, and concentrated.Purification by flash column chromatography (silica gel, 3% MeOH/CH₂Cl₂)gave 51 mg of Cpd 1365. MS m/z (M+H⁺) 524.

Example 51

A. 1-(3-cyano-4-fluoro-phenyl)-indole-5-carboxylic acid, 51a and1-(3-carbamoyl-4-fluoro-phenyl)-indole-5-carboxylic acid, 51b

Intermediates 51a and 51b were prepared according to Example 9e, andwere obtained as a ˜1:1 mixture.

B.2-Fluoro-5-[5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile,Cpd 1417 and2-fluoro-5-[5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzamide,Cpd 1418

Cpd 1417 and Cpd 1418 were prepared according to Example 9 from 5a bisHCl salt (0.22 mmol, 72 mg), the ˜1:1 mixture of 51a and 51b (0.19 mmol,54 mg), HATU (0.22 mmol, 85 mg), and Et₃N (1.11 mmol, 0.15 mL) in 4 mLof CH₂Cl₂. After workup, purification by flash column chromatography(silica gel, 3-4% MeOH/CH₂Cl₂) gave 28 mg (59%) of Cpd 1417 followed by15 mg (31%) of Cpd 1418. Cpd 1417: MS m/z (M+H⁺) 515. Cpd 1418: MS m/z(M+H⁺) 533.

Example 52

A. Methyl 5-Phenyl-benzo[b]thiophene-2-carboxylate, 52b

A mixture of compound 52a (542.3 mg, 2 mmol), phenyl boronic acid 1x(268.2 mg, 2.2 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (98 mg, 0.12 mmol), and K₂CO₃(414.6 mg, 3 mmol), in a dioxane (4 mL)/water (1 mL) mixture, was placedin a capped vial and heated at 80° C. overnight. The reaction mixturewas then diluted with EtOAc and water. The organic layer wasconcentrated under reduced pressure and purified by flash columnchromatography (silica gel, 2-10% EtOAc/heptane) to give compound 52b(510 mg). MS m/z (M+H⁺) 269.1.

B. 5-Phenyl-benzo[b]thiophene-2-carboxylic acid, 52c

A solution of compound 52b (510 mg, 1.9 mmol) and LiOH.H₂O (319 mg, 7.6mmol) in THF/H₂O (10/10 mL) was stirred at room temperature overnight.The resulting mixture was concentrated and diluted with water. The waterlayer was acidified with 1N aqueous HCl to pH˜4 and extracted withCH₂Cl₂. The organic solution was dried over Na₂SO₄ and concentrated togive 52c (479 mg), which was used in the next reaction without furtherpurification. MS m/z (M+H⁺) 255.0.

C. 3-Fluoro-5-phenyl-benzo[b]thiophene-2-carboxylic acid, 52d

To a solution of compound 52c (507 mg, 1.99 mmol) in THF (8 mL) at −70°C. was added n-BuLi (1.6 M in hexane, 2.62 mL, 4.19 mmol). The mixturewas stirred at −70° C. for 1h; then a solution ofN-fluorobenzenesulfonimide (817.3 mg, 2.59 mmol) in THF (2 mL) wasslowly added. The reaction mixture was allowed to warm to roomtemperature and was stirred overnight. The resulting mixture waspartitioned between dilute aqueous HCl and EtOAc. The organic solutionwas washed with water and brine, dried over Na₂SO₄, and concentrated.The residue was tritrated from CH₂Cl₂, filtered and dried the solid togive compound 52d (391.9 mg). MS m/z (M+H⁺) 273.0.

D. 3-Fluoro-5-phenyl-benzo[b]thiophene-2-carbonyl chloride, 52e

To a solution of compound 52d (136.2 mg, 0.5 mmol) in CH₂Cl₂ (5 mL) atroom temperature was added (COCl)₂ (0.064 mL, 0.75 mmol), followed byDMF (0.01 mL, 0.125 mmol). The reaction mixture was stirred at roomtemperature for 18 h. The reaction mixture was then concentrated to givecompound 52e (light pink powder), which was used in the next reactionwithout further purification.

E.1-{1-[(3-Fluoro-5-phenyl-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 1315

To a solution of compound 5e (42.7 mg, 0.131 mmol) and Et₃N (0.07 mL,0.5 mmol) in CH₂Cl₂ (2 mL) at 0° C. was slowly added a solution ofcompound 52e (36.3 mg, 0.125 mmol) in CH₂Cl₂ (1 mL). The reaction wasstirred at 0° C. for 2 h, diluted with CH₂Cl₂, and washed with aqueousNaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by flash column chromatography (silica gel, 2%MeOH/EtOAc) to give compound Cpd 1315 (16.7 mg). ¹H NMR (400 MHz,CDCl₃): δ 7.98 (d, J=1.2 Hz, 1H), 7.89 (d, J=3.2 Hz, 1H), 7.80-7.86 (m,1H), 7.73 (dd, J=8.6, 1.7 Hz, 1H), 7.62-7.68 (m, 2H), 7.55 (d, J=3.2 Hz,1H), 7.46-7.53 (m, 2H), 7.37-7.44 (m, 1H), 4.22-4.67 (m, 5H), 4.05-4.20(m, 1H), 3.77-4.01 (m, 2H), 3.25-3.37 (m, 1H), 2.42-2.68 (m, 4H). MS m/z(M+H⁺) 507.0.

Following the procedure described above for Example 52, and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 10921-[1-({3-Fluoro-5-[4-(trifluoromethyl)phenyl]-1-benzothiophen-2-yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 575.1. 10631-[1-({3-Fluoro-6-[4-(trifluoromethyl)phenyl]-1-benzothiophen-2-yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 575.1.

Example 53

A. 1-tert-Butyl 6-methyl 3-(4-fluorophenyl)-1H-indole-1,6-dicarboxylate,53c

A mixture of compound 53a (1.00 g, 2.49 mmol), 4-fluorophenyl boronicacid 53b (523 mg, 3.74 mmol), Pd(OAc)₂ (44.8 mg, 0.2 mmol),2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos, 204.7 mg, 0.5mmol), and K₃PO₄ (1.06 g, 4.99 mmol), in toluene (5 mL) was placed in acapped vial and heated at 90° C. under N₂ for 3 h. The reaction mixturewas then diluted with EtOAc and water. The organic layer was washed withbrine, concentrated under reduced pressure, and purified by flash columnchromatography (silica gel, 2-10% EtOAc/heptane) to give compound 53c asa light yellow solid, which was further recrystallized from heptane toobtain white solid (707 mg). MS m/z (M+H⁺) 370.2.

B. Methyl 3-(4-fluorophenyl)-1H-indole-6-carboxylate, 53d

To a solution of compound 53c (705 mg, 1.91 mmol) in CH₂Cl₂ (4 mL) wasadded trifluoroacetic acid (1.5 mL) at room temperature. The mixture wasstirred at room temperature for 2 h. The resulting mixture wasconcentrated to give compound 53d (603.3 mg) as a white solid. MS m/z(M+H⁺) 270.1.

C. 3-(4-Fluoro-phenyl)-1H-indole-6-carboxylic acid, 53e

A solution of compound 53d (303 mg, 0.79 mmol), and LiOH.H₂O (132.7 mg,3.16 mmol) in THF/H₂O (10 mL/10 mL) was stirred at 45° C. for 5 h. Theresulting mixture was concentrated and diluted with water. The waterlayer was acidified with 1N aqueous HCl to pH˜4 and extracted withCH₂Cl₂. The organic solution was dried over Na₂SO₄ and concentrated togive 53e (249 mg), which was used in the next reaction without furtherpurification. MS m/z (M+H⁺) 256.0.

D.3-(4-Fluorophenyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole,Cpd 1317

To a mixture of compound 5e (42.9 mg, 0.132 mmol), compound 53e (30.6mg, 0.12 mmol), and Et₃N (0.084 mL, 0.6 mmol) in CH₂Cl₂ (1 mL) at roomtemperature was added HATU (70 mg, 0.168 mmol). The reaction mixture wasstirred at room temperature overnight. The mixture was diluted withCH₂Cl₂ and H₂O, washed with aq. NaHCO₃ and brine, dried over Na₂SO₄,filtered, and concentrated. The residue was purified by flash columnchromatography (silica gel, 2-4% MeOH/EtOAc) to give Cpd 1317 (45.4 mg).¹H NMR (400 MHz, CDCl₃): δ 8.56 (br. s., 1H), 7.83-7.94 (m, 3H),7.57-7.65 (m, 2H), 7.55 (d, J=3.2 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H),7.40-7.45 (m, 1H), 7.13-7.20 (m, 2H), 4.07-4.66 (m, 6H), 3.76-4.01 (m,2H), 3.21-3.36 (m, 1H), 2.38-2.64 (m, 4H). MS m/z (M+H⁺) 490.2.

Following the procedure described above for Example 53, and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Following the procedure described above for Example 53, and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 13163-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 472.2. 13193-(3-Fluorophenyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 490.2.

Example 53a

E. Methyl 3-(4-Fluoro-phenyl)-1-methyl-1H-indole-6-carboxylate, 53f

To a solution of compound 53d (300 mg, 0.78 mmol) in DMF (3 mL) wasadded NaH (60% in mineral oil, 68.9 mg, 1.72 mmol) at 0° C. The mixturewas stirred at 0° C. for 30 min, then CH₃I (0.053 mL, 0.86 mmol) wasadded and stirring continued at 0° C. for another 1 h. The resultingmixture was diluted with EtOAc and water. The organic layer was washedwith brine and concentrated. The residue was recrystallized fromheptane, filtered and dried the solid to give compound 53f (265 mg) as alight yellow solid. MS m/z (M+H⁺) 284.1.

F. 3-(4-Fluoro-phenyl)-1-methyl-1H-indole-6-carboxylic acid, 53g

To a solution compound 53f (264 mg, 0.93 mmol), and LiOH.H₂O (156.4 mg,3.73 mmol) in THF/H₂O (10 mL/10 mL) was stirred at 45° C. for 5 h. Theresulting mixture was concentrated and diluted with water. The waterlayer was acidified with 1N aqueous HCl to pH˜4 and extracted withCH₂Cl₂. The organic solution was dried over Na₂SO₄ and concentrated togive compound 53g (252 mg), which was used in the next reaction withoutfurther purification. MS m/z (M+H⁺) 270.1.

Following the procedure described above for Example 53a and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following intermediate compoundwas prepared:

Following the procedure described above for Example 53 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 13183-(4-Fluorophenyl)-1-methyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole ¹H NMR (400MHz, CDCl₃): δ 7.89 (d, J = 2.9 Hz, 1H), 7.79-7.87 (m, 2H), 7.51-7.63(m, 3H), 7.39 (d, J = 8.3 Hz, 1H), 7.31 (s, 1H), 7.15 (t, J = 8.7 Hz,2H), 4.21-4.67 (m, 5H), 4.08-4.21 (m, 1H), 3.89 (s, 3H), 3.77-3.98 (m,2H), 3.19-3.35 (m, 1H), 2.36-2.65 (m, 4H) MS m/z (M + H⁺) 504.1 11423-(3-Fluorophenyl)-1-methyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 504.1

Example 54

A. Ethyl 1-Methyl-3-phenyl-1H-indazole-5-carboxylate, 54b

A mixture of compound 54a (300 mg, 0.91 mmol), phenyl boronic acid 1x(133 mg, 1.09 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (40 mg, 0.055 mmol), and K₂CO₃(251.2 mg, 1.82 mmol), in a toluene (2 mL)/water (0.4 mL) mixture, wasplaced in a capped vial and heated at 90° C. overnight. The reactionmixture was then diluted with EtOAc and water. The organic layer wasconcentrated under reduced pressure and purified by flash columnchromatography (silica gel, 2-10% EtOAc/Heptanes) to give compound 54b(231 mg). MS m/z (M+H⁺) 281.1.

B. 1-Methyl-3-phenyl-1H-indazole-5-carboxylic acid, 54c

A solution compound 54b (230 mg, 0.58 mmol), and LiOH.H₂O (98 mg, 2.33mmol) in THF/H₂O (10/10 mL) was stirred at 45° C. for 8 h. The resultingmixture was concentrated and diluted with water. The water layer wasacidified with 1N aqueous HCl to pH˜4 and extracted with CH₂Cl₂. Theorganic solution was dried over Na₂SO₄ and concentrated to give 54c (206mg), which was used in the next reaction without further purification.MS m/z (M+H⁺) 253.1.

C.1-Methyl-3-phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indazole,Cpd 1137

To a mixture of compound 5e (42.9 mg, 0.132 mmol), compound 54c (30.3mg, 0.12 mmol), and Et₃N (0.084 mL, 0.6 mmol) in CH₂Cl₂ (1 mL) at roomtemperature was added HATU (70 mg, 0.168 mmol). The reaction mixture wasstirred at room temperature overnight. The mixture was diluted withCH₂Cl₂ and H₂O, washed with aq. NaHCO₃ and brine, dried over Na₂SO₄,filtered, and concentrated. The residue was purified by flash columnchromatography (silica gel, 2-4% MeOH/EtOAc) to give Cpd 1137 (48.1 mg).¹H NMR (400 MHz, CDCl₃): δ 8.32 (s, 1H), 7.94 (d, J=7.3 Hz, 2H), 7.88(d, J=3.2 Hz, 1H), 7.74 (d, J=9.5 Hz, 1H), 7.49-7.58 (m, 3H), 7.39-7.48(m, 2H), 4.16 (s, 3H), 4.09-4.62 (m, 6H), 3.86 (m, 2H), 3.21-3.33 (m,1H), 2.39-2.63 (m, 4H). MS m/z (M+H⁺) 487.2.

Following the procedure described above for Example 54 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Following the procedure described above for Example 54 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 11703-(3-Fluorophenyl)-1-methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole MS m/z(M + H⁺) 505.2 1195 3-(4-Fluorophenyl)-1-methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole MS m/z(M + H⁺) 505.2 11304-Phenyl-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinazoline MS m/z (M + H⁺) 485 10867-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4-[4-(trifluoromethyl)phenyl]quinazoline MS m/z (M + H⁺)553 604 4-Phenyl-7-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinazoline MS m/z (M + H⁺) 478 5977-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4-[4-(trifluoromethyl)phenyl]quinazoline MS m/z (M + H⁺)546

Example 55

A. Methyl 2,3-dihydro-1H-indole-5-carboxylate, 55a

To a solution of methyl 1H-indole-5-carboxylate 1j (2g, 11.4 mmol) inglacial acetic acid (15 mL) at 0° C. was added sodium cyanoborohydride(1.08 g, 17.2 mmol) slowly. The mixture was allowed to warm up andstiffed at room temperature for 2 h. Water was added to the resultingmixture at 0° C., and pH of the solution was adjusted to ˜12 with 1Naqueous NaOH. The mixture was extracted with CH₂Cl₂ and the organiclayer was washed with brine and dried over Na₂SO₄. The solution wasconcentrated and purified by flash column chromatography (silica gel,15% EtOAc/heptane) to give compound 55a (1.79 g). MS m/z (M+H⁺) 178.1.

B. Methyl 1-(4-fluoro-phenyl)-2,3-dihydro-1H-indole-5-carboxylate, 55b,and 1-(4-fluoro-phenyl)-2,3-dihydro-1H-indole-5-carboxylic acid, 55c

A mixture of compound 55a (500 mg, 2.82 mmol), 1-bromo-4-fluoro-benzene1k (0.31 mL, 2.82 mmol), Pd₂(dba)₃ (129 mg, 0.14 mmol), BINAP (132 mg,0.21 mmol), and sodium t-butoxide (325 mg, 3.39 mmol) in toluene (25 mL)was placed in a capped vial and heated at 80° C. overnight. The reactionmixture was then diluted with EtOAc and water, and the water layer wasbasified to pH˜8 with 1N aqueous NaOH. The organic layer wasconcentrated under reduced pressure and purified by flash columnchromatography (silica gel, 5-30% EtOAc/heptane) to give compound 55b(145 mg), MS m/z (M+H⁺) 272.1, and compound 55c (232 mg), MS m/z (M+H⁺)258.0.

C. 1-(4-Fluoro-phenyl)-2,3-dihydro-1H-indole-5-carboxylic acid, 55d

A solution of compound 55b (144 mg, 0.53 mmol) and LiOH.H₂O (89.1 mg,2.12 mmol) in THF/H₂O (5 mL/5 mL) was stiffed at 45° C. overnight. Theresulting mixture was concentrated and diluted with water. The waterlayer was acidified with 1N aqueous HCl to pH˜4 and extracted withCH₂Cl₂. The organic solution was dried over Na₂SO₄ and concentrated togive 55d (138 mg), which was used in the next reaction without furtherpurification. MS m/z (M+H⁺) 258.0.

D.1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3-dihydro-1H-indole,Cpd 885

To a mixture of compound 5e (42.9 mg, 0.132 mmol), compound 55d (30.9mg, 0.12 mmol), and Et₃N (0.084 mL, 0.6 mmol) in CH₂Cl₂ (1 mL) at roomtemperature was added HATU (70 mg, 0.168 mmol). The reaction mixture wasstirred at room temperature overnight. The mixture was diluted withCH₂Cl₂ and washed with H₂O, aqueous NaHCO₃ and brine, and then driedover Na₂SO₄, filtered, and concentrated. The residue was purified byflash column chromatography (silica gel, 2-4% MeOH/EtOAc) to givecompound Cpd 885 (44.4 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J=3.2Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.51 (d, J=1.2 Hz, 1H), 7.38 (dd,J=8.3, 1.7 Hz, 1H), 7.16-7.25 (m, 2H), 7.03-7.12 (m, 2H), 6.88 (d, J=8.3Hz, 1H), 4.05-4.67 (m, 6H), 3.99 (t, J=8.6 Hz, 2H), 3.76-3.94 (m, 2H),3.20-3.30 (m, 1H), 3.16 (t, J=8.6 Hz, 2H), 2.37-2.64 (m, 4H); MS m/z(M+H⁺) 492.1.

Following the procedure described above for Example 55 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following intermediate compoundwas prepared:

Following the procedure described above for Example 55 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 884 1-(4-Fluorophenyl)-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3- dihydro-1H-indoleMS m/z (M + H⁺) 492.1 1081 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3- dihydro-1H-indoleMS m/z (M + H⁺) 492.1 1099 1-(4-Fluorophenyl)-5-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3- dihydro-1H-indoleMS m/z (M + H⁺) 474.1

Example 55a

E. Methyl 1-benzyl-2,3-dihydro-1H-indole-5-carboxylate, 55e

A solution of methyl 2,3-dihydro-1H-indole-5-carboxylate HCl salt 55a(88.6 mg, 0.42 mmol), and benzaldehyde 23a (0.060 mL, 0.55 mmol) inCH₂Cl₂ (4 mL) was stirred at room temperature for 30 min Sodiumtriacetoxyborohydride (159 mg, 0.75 mmol) was added to the mixture andstiffing was continued for 2 h. Water was added to the resulting mixtureat 0° C., and pH of the solution was adjusted to ˜8 with 1N aqueousNaOH. The mixture was extracted with CH₂Cl₂ and the organic layer waswashed with brine and dried over Na₂SO₄. The solution was concentratedand purified by flash column chromatography (silica gel, 10-25%EtOAc/Heptanes) to give 55e (81.3 mg). MS m/z (M+H⁺) 268.0.

F. 1-Benzyl-2,3-dihydro-1H-indole-5-carboxylic acid, 55f

A solution of compound 55e (80.2 mg, 0.3 mmol), and LiOH.H₂O (50.4 mg,1.2 mmol) in THF/H₂O (1.2/1.2 mL) was stiffed at room temperatureovernight. The resulting mixture was concentrated and diluted withwater. The water layer was acidified with 1N aqueous HCl to pH ˜4 andextracted with CH₂Cl₂. The organic solution was dried over Na₂SO₄ andconcentrated to give 55f (60 mg), which was used in the next reactionwithout further purification. MS m/z (M+H⁺) 254.1.

G.1-Benzyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3-dihydro-1H-indole,Cpd 994

To a solution of compound 5e (89.5 mg, 0.261 mmol), compound 55f (60 mg,0.237 mmol), and EDC (68.1 mg, 0.356 mmol) in CH₂Cl₂ (5 mL) was addedEt₃N (0.1 mL, 0.711 mmol). The reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with CH₂Cl₂ and H₂O andthe water layer was acidified to pH ˜6 with 1 N aqueous HCl. The organicsolution was dried over Na₂SO₄ and concentrated. The residue waspurified by reverse phase chromatography to give Cpd 994 as a TFA salt(40.4 mg). ¹H NMR (400 MHz, CD₃OD): δ 7.98 (d, J=3.2 Hz, 1H), 7.89 (d,J=3.2 Hz, 1H), 7.36-7.44 (m, 2H), 7.29-7.36 (m, 4H), 7.22-7.29 (m, 1H),6.52 (d, J=8.3 Hz, 1H), 4.39-4.91 (m, 6H), 4.38 (s, 2H), 3.99-4.23 (m,3H), 3.48 (t, J=8.6 Hz, 2H), 3.42 (br. s., 4H), 3.01 (t, J=8.6 Hz, 2H).MS m/z (M+H⁺) 488.1.

Following the procedure described above for Example 55a and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Following the procedure described above for Example 55a and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 8815-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[3-(trifluoromethyl)benzyl]-2,3-dihydro- 1H-indole MSm/z (M + H⁺) 556.0 8825-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)benzyl]-2,3-dihydro- 1H-indole MSm/z (M + H⁺) 556.0

Example 55b

H. 1-Benzoyl-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester, 55g

To a solution of methyl 2,3-dihydro-1H-indole-5-carboxylate HCl salt 55a(64.1 mg, 0.3 mmol), and benzoyl chloride 1t (0.042 mL, 0.36 mmol) inCH₂Cl₂ (1 mL) was added Et₃N (0.13 mL, 0.9 mmol) at 0° C. The reactionmixture was stirred at 0° C. for 2 h. The resulting mixture waspartitioned between CH₂Cl₂ and H₂O. The organic solution was dried overNa₂SO₄ and concentrated. Purification of the residue by flash columnchromatography (silica gel, 10-20% EtOAc/Heptanes) gave 55g (88 mg). MSm/z (M+H⁺) 282.0.

I. 1-Benzoyl-2,3-dihydro-1H-indole-5-carboxylic acid, 55h

A solution of compound 55g (87 mg, 0.31 mmol), and LiOH.H₂O (52 mg, 1.24mmol) in THF/H₂O (2/2 mL) was stirred at room temperature overnight. Theresulting mixture was concentrated and diluted with water. The waterlayer was acidified with 1N aqueous HCl to pH ˜6 and extracted withCH₂Cl₂. The organic solution was dried over Na₂SO₄ and concentrated togive 55h (82 mg), which was used in the next reaction without furtherpurification. MS m/z (M+H⁺) 268.0.

J.1-(Phenylcarbonyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3-dihydro-1H-indole,Cpd 724

To a solution of compound 5e (115.9 mg, 0.34 mmol), compound 55h (82 mg,0.31 mmol) and EDC (87.9 mg, 0.46 mmol) in CH₂Cl₂ (5 mL) was added Et₃N(0.13 mL, 0.92 mmol). The reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with CH₂Cl₂ and H₂O andthe water layer was acidified to pH ˜6 with 1 N aqueous HCl. The organicsolution was dried over Na₂SO₄ and concentrated. The residue waspurified by flash column chromatography (silica gel, 2% MeOH/EtOAc) togive compound Cpd 724 (64.4 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d,J=3.2 Hz, 1H), 7.31-7.63 (m, 9H), 4.38-4.63 (m, 2H), 4.03-4.37 (m, 6H),3.74-3.96 (m, 2H), 3.20-3.29 (m, 1H), 3.16 (t, J=8.3 Hz, 2H), 2.38-2.61(m, 4H). MS m/z (M+H⁺) 502.0.

Following the procedure described above for Example 55b and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following intermediate compoundwas prepared:

Following the procedure described above for Example 55b and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compound of the presentinvention was prepared:

Cpd Cpd Name and Data 7731-(Cyclopropylcarbonyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3- dihydro-1H-indoleMS m/z (M + H⁺) 466.0

Example 56

A. Methyl 3-Benzyl-1-methyl-1H-indole-6-carboxylate, 56c

To a solution of compound 56a (500 mg, 2.64 mmol) and benzyl chloride56b (0.33 mL, 2.91 mmol) in dioxane (5 mL) was added silver oxide (673.6mg, 2.91 mmol). The mixture was stirred at 80° C. overnight. Theresulted mixture was filtered through celite and washed with EtOAc. Thefiltrate was concentrated and purified by flash column chromatography(silica gel, 20-60% CH₂Cl₂/Heptanes) to give compound 56c (168 mg). MSm/z (M+H⁺) 280.2.

B. 3-Benzyl-1-methyl-1H-indole-6-carboxylic acid, 56d

To a solution compound 56c (168 mg, 0.60 mmol), and LiOH.H₂O (101 mg,2.41 mmol) in THF/H₂O (3/3 mL) was stirred at room temperature for 6 h.Concentrated the resulted mixture, extracted the residue with CH₂Cl₂,H₂O, acidified the water layer with 1N HCl(aq) to pH˜4. The organicsolution was dried over Na₂SO₄ and concentrated to give 56d (172.2 mg),which was used in the next reaction without further purification. MS m/z(M+H⁺) 266.2.

C.3-Benzyl-1-methyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole,Cpd 753

To a mixture of compound 5e (71.6 mg, 0.22 mmol), compound 56d (53.1 mg,0.2 mmol), and Et₃N (0.14 mL, 1.0 mmol) in CH₂Cl₂ (1 mL) at roomtemperature was added HATU (106.5 mg, 0.28 mmol). The reaction mixturewas stirred at room temperature overnight. The mixture was diluted withCH₂Cl₂ and H₂O, washed with aqueous NaHCO₃ and brine, dried over Na₂SO₄,filtered, and concentrated. Purification of the residue by flash columnchromatography (silica gel, 2-4% MeOH/EtOAc) gave compound Cpd 753 (20.8mg). ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J=2.4 Hz, 1H), 7.74 (s, 1H),7.55 (d, J=2.7 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.15-7.35 (m, 6H), 6.89(s, 1H), 4.06-4.60 (m, 8H), 3.79-3.98 (m, 2H), 3.78 (s, 3H), 3.17-3.31(m, 1H), 2.35-2.64 (m, 4H). MS m/z (M+H⁺) 500.3.

Following the procedure described above for Example 56 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Following the procedure described above for Example 56 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 10263-(4-Fluorobenzyl)-1-methyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 518.1 1027 3-(4-Fluorobenzyl)-1-methyl-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 518.1 1028 3-(4-Fluorobenzyl)-1-methyl-6-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 500.1 1033 3-(3-Fluorobenzyl)-1-methyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole m/z (M + H⁺)518.2

Example 57

5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3,3-tris[3-(trifluoromethyl)benzyl]-1,3-dihydro-2H-indol-2-one,Cpd 1430

To a solution of Cpd 918 from Example 9) (25 mg, 0.061 mmol) and K₂CO₃(16.9 mg, 0.122 mmol) in DMF (0.8 mL) was added 3-trifluoromethyl-benzylbromide (20.4 mg, 0.085 mmol). The mixture was stirred at roomtemperature overnight. The resulting mixture was extracted with EtOAcand H₂O. The organic solution was dried over Na₂SO₄ and concentrated.The residue was purified by reverse phase chromatography to give Cpd1430 as a TFA salt (3.6 mg), MS m/z (M+H⁺) 885.9.

Following the procedure described above for Example 57 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 1431 1,3,3-Tribenzyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-indol-2-one MS m/z (M + H⁺) 682.0 9925-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3,3-bis[3-(trifluoromethyl)benzyl]-1,3-dihydro-2H-indol-2-one MS m/z (M + H⁺) 728.0

Example 58

5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole,Cpd 911, and1-(2,3-Dihydro-1H-indol-5-ylcarbonyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole,Cpd 988

To a solution of compound 5e (300 mg, 0.92 mmol), a mixture of2,3-dihydro-1H-indole-5-carboxylic acid HCl salt 58a (101 mg, 0.51 mmol)and 1H-indole-5-carboxylic acid HCl salt 58b (100 mg, 0.51 mmol), andEDC (265 mg, 1.38 mmol) in CH₂Cl₂ (10 mL) was added Et₃N (0.39 mL, 2.77mmol). The reaction mixture was stirred at room temperature overnight.The resulting mixture was extracted with CH₂Cl₂ and washed with H₂O. Theorganic solution was dried over Na₂SO₄ and concentrated. The residue waspurified by reverse phase chromatography to give Cpd 911 as a TFA salt(89.4 mg) and Cpd 988 as a TFA salt (13.8 mg).

Cpd 911: ¹H NMR (400 MHz, CD₃OD): δ 10.93 (br. s., 1H), 7.98 (d, J=3.2Hz, 1H), 7.95 (s, 1H), 7.89 (d, J=3.2 Hz, 1H), 7.47 (s, 2H), 7.36 (d,J=3.2 Hz, 1H), 6.57 (d, J=2.9 Hz, 1H), 4.25-4.84 (m, 6H), 3.91-4.15 (m,4H), 2.80 (br. s., 4H). MS m/z (M+H⁺) 396.0. Cpd 988: ¹H NMR (400 MHz,CD₃OD): δ 7.98 (d, J=3.2 Hz, 1H), 7.88 (d, J=3.2 Hz, 1H), 7.85 (d, J=1.0Hz, 1H), 7.58 (s, 1H), 7.27-7.56 (m, 5H), 6.56 (d, J=3.2 Hz, 1H),4.29-4.89 (m, 6H), 4.20 (t, J=8.3 Hz, 2H), 3.96-4.15 (m, 3H), 3.32-3.43(m, 4H), 3.17 (t, J=8.3 Hz, 2H). MS m/z (M+H⁺) 541.0.

Example 59

A. 3-Methyl-[1,1′-biphenyl]-4-carboxylic acid, 59b

The title compound 59b was prepared using the method described inExample 6, Step F, substituting 4-bromo-2-methylbenzoic acid 59a for Cpd173 and substituting phenylboronic acid 1x for compound 6e. The crudeproduct 59b was purified by reverse phase chromatography. MS m/z (M+H⁺)213.1.

B.1-{1-[(3-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine,Cpd 619

The title compound Cpd 619 was prepared using the method described inExample 9, substituting compound 59b for compound 9c and substitutingcompound 2c for compound 5e. The crude compound Cpd 619 was purified byreverse phase chromatography. MS m/z (M+H⁺) 440.1.

Following the procedure described above for Example 59 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Following the procedure described above for Example 59 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 6131-{1-[(2-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 440.2 6141-{1-[(3-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 444.1 6151-{1-[(2-Methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 456.1 6121-{1-[(3-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 460.2 7061-(1-{[4-(2,2,6,6-Tetramethyl-3,6-dihydro-2H-pyran-4-yl)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 495.3 10741-{1-[(3-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine 1H NMR (300 MHz, CD₃OD): δ 7.97 (d,1H), 7.87 (d, 1H), 7.33-7.66 (m, 8H), 4.62-4.76 (m, 2H), 4.38-4.51 (m,1H), 4.13-4.35 (m, 3H), 3.84-4.07 (m, 3H), 3.02-3.19 (m, 4H), 2.47 (s,1H) MS m/z (M + H⁺) 447.1 13221-{1-[(2-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine 1H NMR (300 MHz, CD₃OD): δ 7.98 (d,1H), 7.88 (d, 1H), 7.59 (s, 1H), 7.54 (dd, 1H), 7.27-7.49 (m, 6H),4.61-4.78 (m, 3H), 4.39-4.61 (m, 2H), 4.33 (M, 1H), 3.88-4.11 (m, 3H),3.10-3.26 (m, 4H), 2.30 (s, 3H) MS m/z (M + H⁺) 447.1 14051-{1-[(3-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine 1H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H),7.87 (d, 1H), 7.36-7.73 (m, 8H), 4.23-4.76 (m, 6H), 3.85-4.07 (m, 3H),3.04-3.20 (m, 4H) MS m/z (M + H⁺) 451.2 13771-{1-[(2-Methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 463.2 13231-{1-[(3-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 467.1 14061-{1-[(2-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 447.1 11081-{1-[(3-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine 1H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H),8.22 (d, 1H), 7.38-7.71 (m, 8H), 4.28-4.53 (m, 4H), 3.94-4.25 (m, 5H),3.16-3.27 (m, 4H) MS m/z (M + H⁺) 451.1 12531-{1-[(2-Methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 463.2 12211-{1-[(3-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 467.1 11851-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[2′-(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 501.0 1278 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[4′-(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 501.0 12501-{1-[(4′-Methoxybiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 563.0 10911-{1-[(4′-Methoxybiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 463.0 10931-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[3′-(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 501.0 11241-{1-[(3′-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 451.0 11171-{1-[(2′,4′-Difluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine 1H NMR (300 MHz, CD₃OD): δ 7.97 (d,1H), 7.87 (d, 1H), 7.80 (d, 1H), 7.66-7.75 (m, 2H), 7.50-7.64 (m, 2H),7.05- 7.16 (d, 1H), 4.24-4.75 (m, 6H), 3.83-4.06 (m, 3H), 3.02- 3.18 (m,4H) MS m/z (M + H⁺) 469.0 1188 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[3′-(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 501.0 12281-{1-[(3′-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 451.0 12391-{1-[(2′,4′-Difluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 469.0 11721-{1-[(2-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 451.0 12001-{1-[(4-Chlorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 467.0 11681-{1-[(6-Methoxybiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 463.0 12341-{1-[(2-Methylbiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 447.0 12401-{1-[(2-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 451.0 12881-{1-[(4-Chlorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 467.0 12651-{1-[(6-Methoxybiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 463.0 12851-{1-[(2-Methylbiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 447.0 12081-{1-[(4-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 451.0 12801-{1-[(4-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 451.0 11441-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[5-(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3- yl)piperazine 1H NMR(300 MHz, CD₃OD): δ 8.12 (s, 1H), 8.07 (s, 1H), 7.96 (d, 1H), 7.92 (s,1H), 7.86 (d, 1H), 7.67-7.74 (m, 2H), 7.42-7.57 (m, 3H), 4.57-4.74 (m,3H), 4.38-4.55 (m, 2H), 4.33 (m, 1H), 3.91-4.02 (m, 2H), 3.85 (m, 1H),3.01-3.13 (m, 4H) MS m/z (M + H⁺) 501.0 11041-{1-[(5-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H),7.88 (d, 1H), 7.64-7.74 (m, 3H), 7.56-7.63 (dt, 1H), 7.35-7.53 (m, 4H),4.31-4.83 (m, 6H), 3.94-4.10 (m, 3H), 3.19-3.27 (m, 4H) MS m/z (M + H⁺)451.0 1259 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[5-(trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3- yl)piperazine MS m/z(M + H⁺) 501.0 12731-{1-[(5-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 451.0 11141-(Isothiazol-5-ylcarbonyl)-4-(1-{[2-methyl-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine ¹H NMR(400 MHz, CDCl₃): δ 8.56 (d, 1H); 7.92 (d, 1H); 7.78-7.56 (m, 5H); 7.46(m, 1H); 4.45 (m, 1H); 4.41-4.19 (m, 3H); 3.94 (bs, 5H); 3.12 (bs, 4H);2.5 (s, 3H) MS m/z (M + H⁺) 515.2 11381-(1H-Pyrrol-2-ylcarbonyl)-4-[1-({4-[5-(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)azetidin-3- yl]piperazineMS m/z (M + H⁺) 489 1268 1-(1,3-Thiazol-5-ylcarbonyl)-4-[1-({4-[5-(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)azetidin-3- yl]piperazineMS m/z (M + H⁺) 507.1

Example 59a

Following the procedure described above for Example 2 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 12121-{[3-Methyl-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}-4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺)515.12 1136 1-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]-4-({4-[5-(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)piperazine MS m/z (M +H⁺) 507.05 12601-{[3-Methyl-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}-4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺)515.2 1161 1-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]-4-({4-[5-(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)piperazine MS m/z (M +H⁺) 507.1 1162 1-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-yl]-4-({4-[5-(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)piperazine MS m/z (M +H⁺) 489.2

Example 60

A. Methyl 4-((4-fluorophenyl)amino)-3-nitrobenzoate, 60c

A mixture of methyl 4-fluoro-3-nitrobenzoate 60a (1 g, 5.02 mmol),4-fluoroaniline 60b (4.34 mL, 5.02 mmol), and DIPEA (1.04 mL, 6.03 mmol)in DMF (10 mL) was stirred at room temperature for 2 h. Water was addedto the mixture; the resulting solid was filtered, washed with water, anddried. The crude product 60c was used in the next reaction withoutpurification.

B. Methyl 3-amino-4-((4-fluorophenyl)amino)benzoate, 60d

A mixture of 60c (1.4 g, 4.8 mmol) and SnCl₂.2H₂O (4.9 g, 21.7 mmol) inEtOH (50 mL) was stirred at 80° C. After 4 h, the mixture was cooled toroom temperature and was slowly added to saturated aqueous NaHCO₃. Thesolid was filtered and washed with H₂O. The solid was triturated withEtOAc and the filtrate was concentrated. The crude product 60d was usedin the next reaction without purification. MS m/z (M+H⁺) 261.1.

C. Methyl 1-(4-fluorophenyl)-1H-benzo[d]imidazole-5-carboxylate, 60e

A mixture of 60d (0.18 g, 0.693 mmol) and trimethyl orthoformate (0.7mL, 6.39 mmol) in DMF (2 mL) was refluxed for 5 h and then cooled toroom temperature. Water was added to the mixture. The resulting solidwas filtered, washed, with water, and dried. The crude product 60e wasused in the next reaction without purification. MS m/z (M+H⁺) 271.1.

D. 1-(4-Fluorophenyl)-1H-benzo[d]imidazole-5-carboxylic acid, 60f

To a solution of 60e (0.18 g, 0.666 mmol) in EtOH (10 mL) was added 1Naqueous NaOH (2.5 mL, 2.5 mmol). The mixture was stirred at roomtemperature for 4 d. The solvent was evaporated and 1N aqueous HCl wasadded, followed by extraction with EtOAc. The organic layer was driedover MgSO₄ and concentrated. The crude product 60f was purified bypreparative reverse phase chromatography. MS m/z (M+H⁺) 257.1.

E.1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole,Cpd 1167

To a solution of 5e (0.058 g, 0.178 mmol) and HATU (0.081 g, 0.214 mmol)in CH₂Cl₂ (3 mL) was added Et₃N (0.099 mL, 0.713 mmol). The mixture wasstirred at room temperature for 30 min, and then 60f (0.050 g, 0.196mmol) was added. The reaction mixture was stirred at room temperatureovernight. Water (6 mL) was added and the mixture was extracted withEtOAc. The organic layer was dried over MgSO₄ and concentrated. Thecrude product Cpd 1167 was purified by preparative reverse phasechromatography. MS m/z (M+H⁺) 491.2.

Following the procedure described above for Example 60 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared.

Following the procedure described above for Example 60 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared.

Cpd Cpd Name and Data 11861-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 509.2 10645-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H- benzimidazole 1H NMR(300 MHz, CD₃OD): d 8.82 (s, 1H), 8.14 (s, 1H), 7.96-8.03 (m, 3H),7.86-7.95 (m, 3H), 7.76-7.85 (m, 2H), 7.08 (d, 1H), 4.36-4.86 (m, 6H),3.97-4.16 (m, 3H), 3.32- 3.42 (m, 4H) MS m/z (M + H⁺) 541.2 7615-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1H-benzimidazole MS m/z (M + H⁺)479.1 780 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1H-benzimidazole MS m/z (M +H⁺) 493.2 759 1-(4,4-Difluorocyclohexyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 515.2 12811-Phenyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 473.2 12741-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 491.2 1270 1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 509.1 12315-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H- benzimidazole MS m/z(M + H⁺) 541.2 8415-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1H-benzimidazole MS m/z (M + H⁺)479.1 851 5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1H-benzimidazole MS m/z (M +H⁺) 493.2 834 1-(4,4-Difluorocyclohexyl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 515.2 12071-Phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 473

Example 60a

F. Methyl2-methyl-1-(4-fluorophenyl)-1H-benzo[d]imidazole-5-carboxylate, 60g

The title compound 60g was prepared using the method described inExample 60, substituting trimethyl orthoacetate for trimethylorthoformate in Step C. The crude product 60g was used in the nextreaction without purification. MS m/z (M+H⁺) 285.1.

G. 2-Methyl-1-(4-fluorophenyl)-1H-benzo[d]imidazole-5-carboxylate, 60h

The title compound 60h was prepared using the method described inExample 60, substituting 60g for 60e in Step D. The crude product 60hwas used in the next reaction without purification. MS m/z (M+H⁺) 271.2.

H. Cpd 1227

The title compound Cpd 1227 was prepared using the method described inExample 60, substituting 60h for 60f in Step E. The crude product Cpd1227 was purified by preparative reverse phase chromatography. MS m/z(M+H⁺) 505.2.

Following the procedure described above for Example 60a and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared.

Following the procedure described above for Example 60a and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared.

Cpd Cpd Name and Data 1229 2-Methyl-1-phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 487.2 12061-(3,4-Difluorophenyl)-2-methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 523.2 12152-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-benzimidazole MS m/z (M + H⁺) 555.2 7892-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1H- benzimidazole MSm/z (M + H⁺) 493.2 7772-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1H- benzimidazoleMS m/z (M + H⁺) 507.2 7981-(4,4-Difluorocyclohexyl)-2-methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 529.2 12911-(4-Fluorophenyl)-2-methyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 505.2 1296 2-Methyl-1-phenyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 487.2 12641-(3,4-Difluorophenyl)-2-methyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 523.2 12892-Methyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-benzimidazole MS m/z (M + H⁺) 555.2 8582-Methyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1H- benzimidazole MSm/z (M + H⁺) 493.2 8662-Methyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1H- benzimidazoleMS m/z (M + H⁺) 507.1 15061-(4,4-Difluorocyclohexyl)-2-methyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MSm/z (M + H⁺) 529.2 6352-Methyl-1-phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 480

Example 60b

I. Methyl1-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate,60i

A mixture of 60d (0.20 g, 0.826 mmol) and 1,1′-carbonyldiimidazole(0.535 g, 3.3 mmol) in DMF (8 mL) was heated at 90° C. for 2 h. Thesolvent was removed and the residue was triturated with water (15 mL).The resulting precipitate was collected by filtration and washed severaltimes with water. The crude product 60i was used in the next reactionwithout further purification. MS m/z (M+H⁺) 287.1.

J.1-(4-Fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate,60j

The title compound 60j was prepared using the method described inExample 60, substituting 60i for 60e in Step D. The crude product 60jwas used in the next reaction without purification. MS m/z (M+H⁺) 273.1.

K.1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-benzimidazol-2-one,Cpd 934

The title compound Cpd 934 was prepared using the method described inExample 60, substituting 60j for 60f in Step E. The crude product Cpd934 was purified by preparative reverse phase chromatography. MS m/z(M+H⁺) 507.1.

Following the procedure described above for Example 60b and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared.

Following the procedure described above for Example 60b and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared.

Cpd Cpd Name and Data 9331-Phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-benzimidazol-2-one ¹H NMR (300MHz, CD₃OD): δ 7.97 (d, 1H), 7.88 (d, 1H), 7.56-7.66 (m, 2H), 7.46-7.55(m, 4H), 7.42 (dd, 1H), 7.08 (d, 1H), 4.26-4.81 (m, 6H), 3.93-4.10 (m,3H), 3.18-3.27 (m, 4H) MS m/z (M + H⁺) 489.1 9321-(4,4-Difluorocyclohexyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-benzimidazol-2-one MS m/z (M + H⁺) 531.0 9351-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-benzimidazol-2-one MS m/z (M + H⁺) 525.1 9365-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1,3-dihydro-2H-benzimidazol-2-one MS m/z (M + H⁺) 557.0 9375-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzimidazol-2-one MS m/z (M + H⁺) 495.1 9385-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1,3-dihydro-2H-benzimidazol-2-one MS m/z (M + H⁺) 509.1 9391-Phenyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-benzimidazol-2-one MS m/z (M +H⁺) 489.1 940 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-benzimidazol-2-one MS m/z (M + H⁺) 507.1 9411-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-benzimidazol-2-one MS m/z (M + H⁺) 525.2 9425-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1,3-dihydro-2H-benzimidazol-2-one MS m/z (M + H⁺) 557.2 9435-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzimidazol-2-one MS m/z (M + H⁺) 495.2 9445-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1,3-dihydro-2H-benzimidazol-2-one MS m/z (M + H⁺) 509.2 9451-(4,4-Difluorocyclohexyl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-benzimidazol-2-one MS m/z (M + H⁺) 531.2

Example 61

A. 3-Fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid, 61a

A solution of 6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid 10a(2.031 mmol, 0.50 g) in THF (8 mL) at −70° C. was treated with a 1.6 Msolution of n-BuLi in hexanes (4.26 mmol, 2.66 mL). After 1 h at −70°C., N-fluorobenzenesulfonimide (2.64 mmol, 0.833 g) in THF (2 mL) wasslowly added and the reaction was warmed to room temperature. After 1 hthe mixture was partitioned between dilute aqueous HCl and EtOAc. Theorganic layer was washed with water and brine, and then concentrated.The residue was triturated with CH₂Cl₂. The off-white precipitate wasfiltered and collected to provide 61a.

B. 3-Fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride, 61b

The title compound 61b was prepared using the method described inExample 10, substituting 61a for 10a in Step A.

C.1-(1-{[3-Fluoro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 895

The title compound Cpd 895 was prepared using the method described inExample 10, substituting 61b for 10b in Step B. MS m/z (M+H⁺) 499.

Following the procedure described above for Example 61 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 6531-(1-{[3-Fluoro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z(M + H⁺) 499 509 1-(1-{[3-Fluoro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺)492

Example 62

A. 1-tert-Butyl 6-methyl 3-phenyl-1H-indole-1,6-dicarboxylate, 62b

A mixture of 1-tert-butyl 6-methyl 3-iodo-1H-indole-1,6-dicarboxylate62a (5.02 mmol, 2.016 g), phenylboronic acid 1x (7.53 mmol, 0.92 g),Pd(OAc)₂ (0.402 mmol, 90 mg), Sphos 0.904 mmol, (0.37 g), and K₃PO₄(10.1 mmol, 2.13 g) in toluene (10 mL) in sealed reaction vial wasstirred at room temperature for 2 min and then heated at 90° C. under N₂for 4 h. The reaction mixture was quenched with EtOAc and water. Theorganic layer was concentrated and purified by flash columnchromatography (silica gel, 8% EtOAc/hexanes). The desired product wascollected as a light yellow solid that was washed with small amount ofhexanes to obtain 62b as a white solid.

B. Methyl 3-phenyl-1H-indole-6-carboxylate TFA salt, 62c

To a solution of 1-tert-butyl 6-methyl3-phenyl-1H-indole-1,6-dicarboxylate 62b (4.04 mmol, 1.42 g) in CH₂Cl₂(8 mL) was added 6 mL of TFA. The resulting solution was stiffed for 3h. The mixture was then concentrated and washed with hexanes to afford62c.

C. Methyl 1-methyl-3-phenyl-1H-indole-6-carboxylate, 62d

NaH (60% dispersion in mineral oil, 4.52 mmol, 186 mg) was addedportion-wise to a solution of methyl 3-phenyl-1H-indole-6-carboxylateTFA salt 62c (2.07 mmol, 757 mg) in DMF at 0° C. and the mixture wasstirred for 20 min. Methyl iodide (2.28 mmol, 0.14 mL) was added and thereaction mixture was maintained at 0° C. for 1 h. Water was then addedand the reaction was extracted with EtOAc. The organics wereconcentrated and purified by flash column chromatography (silica gel,15% EtOAc/hexanes) to give 62d.

D. 1-Methyl-3-phenyl-1H-indole-6-carboxylic acid, 62e

The title compound 62e was prepared using the method described inExample 29, substituting 62d for 29c in Step B.

E.1-Methyl-3-phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole,Cpd 1132

The title compound Cpd 1132 was prepared using the method described inExample 9, substituting 62d for 9c in Step D. MS m/z (M+H⁺) 486.

Following the procedure described above for Example 62 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Following the procedure described above for Example 62 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 701 3-Iodo-1-methyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 536 1084 1-Methyl-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]- 1H-indole MSm/z (M + H⁺) 554 11481-Methyl-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3-[4-(trifluoromethyl)phenyl]- 1H-indole MSm/z (M + H⁺) 554 11001-Methyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]- 1H-indole MSm/z (M + H⁺) 554 13471-Methyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3-[4-(trifluoromethyl)phenyl]- 1H-indole MSm/z (M + H⁺) 554 1155 1-Methyl-3-phenyl-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 486 593 1-Methyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺)547 585 1-Methyl-3-phenyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 479

Example 62a

F. 1-tert-Butyl 6-methyl3-(3-(trifluoromethyl)phenyl)-1H-indole-1,6-dicarboxylate, 62g

The title compound 62g was prepared using the method described inExample 62, substituting 62f for 1x in Step A.

G. Methyl 3-(3-(trifluoromethyl)phenyl)-1H-indole-6-carboxylate TFAsalt, 62h

The title compound 62h was prepared using the method described inExample 62, substituting 62g for 62b in Step B.

H. 3-(3-(Trifluoromethyl)phenyl)-1H-indole-6-carboxylic acid, 62i

The title compound was prepared using the method described in Example62, substituting 62h for 62e in Step D.

E.6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]-1H-indole,Cpd 1341

The title compound Cpd 1341 was prepared using the method described inExample 9, substituting 62i for 9c in Step D. MS m/z (M+H⁺) 540.

Following the procedure described above for Example 62a and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following intermediate compoundwas prepared:

Following the procedure described above for Example 62a and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 5726-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺) 533634 6-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3-[4-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺) 5331340 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3-[4-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺)540 1344 6-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3-[4-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺)540 1345 6-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺)540

Example 63

A. Methyl 4-(hydroxy(4-(trifluoromethyl)phenyl)methyl)benzoate, 63c

To a solution of methyl 4-iodobenzoate 63a (8 mmol, 2.1 g) in 10 mL ofdry THF was added i-propyl magnesium chloride (2M in THF, 8.4 mmol, 4.2mL) dropwise under N₂ at −20° C. The solution was stiffed for 30 min.The formed Grignard reagent in THF was then added slowly to a solutionof 4-trifluoromethylbenzaldehyde (8 mmol, 1.1 mL) in THF (20 mL) at −40°C. After 20 min, the reaction mixture was allowed to warm up slowly toroom temperature. The reaction was quenched with saturated aqueous NH₄Cland extracted with EtOAc. The organic layer was concentrated andpurified by flash column chromatography (silica gel, 15% EtOAc/hexanes)to give the 63c as white solid.

B. 4 Methyl 4-(fluoro(4-(trifluoromethyl)phenyl)methyl)benzoate, 63d

To a solution of 63c (0.97 mmol, 300 mg) in CH₂Cl₂ was added DAST (1.015mmol, 0.133 mL) dropwise at −78° C. under N₂. The reaction was kept at−78° C. for 30 min and then quenched with aqueous NaHCO₃ solution at lowtemperature. Additional CH₂Cl₂ was added to the reaction and the organicsolution was concentrated. The crude material was purified flash columnchromatography (silica gel, 10% EtOAc/hexanes) to give 63d.

C. 4-(Fluoro(4-(trifluoromethyl)phenyl)methyl)benzoic acid, 63e

The title compound was prepared using the method described in Example29, substituting 63d for 29c in Step B.

D.1-[1-[(4-{Fluoro[4-(trifluoromethyl)phenyl]methyl]phenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 982

The title compound Cpd 982 was prepared using the method described inExample 9, substituting 63e for 9c in Step D. MS m/z (M+H⁺) 533.

Example 64

A. Methyl 4-(2-phenyl-1,3-dithiolan-2-yl)benzoate, 64b

Methyl 4-benzoylbenzoate 64a (2.08 mmol, 0.50 g) and BF₃.(OAc)₂ (5.2mmol, 0.73 mL) were dissolved in dry CH₂Cl₂ under N₂. Ethane-1,2-dithiol(3.95 mmol, 0.333 mL) was added and the solution was stiffed overnight.The reaction mixture was partitioned between CH₂Cl₂ and water. Theorganic layer was concentrated and purified by flash columnchromatography (silica gel, 10% EtOAc/hexanes) to afford compound 64b.B. Methyl 4-(difluoro(phenyl)methyl)benzoate, 64c

Selectfluor (1.07 mmol, 381 mg) and HF-pyridine reagent (1.5 mL, HF:Pyridine=70:30 wt %) were dissolved in CH₂Cl₂ (4 mL) in a polyethylenebottle and cooled to 0° C. A solution of 64b (0.512 mmol, 162 mg) inCH₂Cl₂ (2 mL) was slowly added and the mixture was stiffed for 45 min atroom temperature. When TLC indicated the consumption of all 64b, thereaction was diluted with CH₂Cl₂. The combined organics were dried overanhydrous Na₂SO₄ and concentrated. The crude product was purified byflash column chromatography (silica gel, 5% EtOAc/hexanes) to affordcompound 64c as a clear oil.

C. 4-(Difluoro(phenyl)methyl)benzoic acid, 64d

The title compound 64d was prepared using the method described inExample 29, substituting 64c for 29c in Step B.

D.1-[1-({4-[Difluoro(phenyl)methyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 986

The title compound Cpd 986 was prepared using the method described inExample 9, substituting 64d for 9c in Step D. MS m/z (M+H⁺) 483.

Example 65

A. Methyl 3-cyclopropyl-6-fluorobenzo[b]thiophene-2-carboxylate, 65c

A mixture of methyl 3-chloro-6-fluorobenzo[b]thiophene-2-carboxylate 65a(0.613 mmol, 150 mg), cyclopropylboronic acid 65b (0.92 mmol, 79 mg),Pd(OAc)₂ (0.09 mmol, 20 mg), SPhos (0.215 mmol, 88 mg), and K₃PO₄ (1.23mmol, 0.26 g) in toluene (2 mL) was heated to 100° C. for 3 h in asealed reaction vessel. The reaction was diluted with EtOAc and water.The organic layer was concentrated and purified by flash columnchromatography (silica gel, 10% EtOAc/hexanes) to give compound 65c.

B. 3-Cyclopropyl-6-fluoro-benzo[b]thiophene-2-carboxylic acid, 65d

The title compound 65d was prepared using the method described inExample 29, substituting 65c for 29c in Step B.

C. 3-Cyclopropyl-6-fluoro-benzo[b]thiophene-2-carbonyl chloride, 65e

The title compound 65e was prepared using the method described inExample 10, substituting 65d for 10a in Step A.

D.1-{1-[(3-Cyclopropyl-6-fluoro-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 714

The title compound Cpd 714 was prepared using the method described inExample 10, substituting 65e for 10b in Step B. MS m/z (M+H⁺) 471.

Following the procedure described above for Example 65 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following intermediate compoundwas prepared:

Following the procedure described above for Example 65 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 6951-{1-[(3-Cyclobutyl-6-fluoro-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 485 528 1-{1-[(3-Cyclopropyl-6-fluoro-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺)464 513 1-{1-[(3-Cyclobutyl-6-fluoro-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺)478 1346 1-{1-[(3-Methyl-5-phenyl-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine NMR(CDCl₃) δ: 7.96 (d, J = 1.2 Hz, 1H), 7.84-7.93 (m, 2H), 7.62-7.74 (m,3H), 7.55 (d, J = 3.2 Hz, 1H), 7.49 (m, 2H), 7.34-7.44 (m, 1H),4.12-4.47 (m, 6H), 3.87 (m, 2H), 3.19-3.35 (m, 1H), 2.69 (s, 3H), 2.50(m, 4H) MS m/z (M + H⁺) 503 10581-{1-[(3-Methyl-5-phenyl-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine; MSm/z (M + H+) 503 6911-(1-{[5-Methyl-3-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine; MSm/z (M + H+) 495 7371-(1-{[5-Methyl-3-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine; MSm/z (M + H+) 495 7071-(1-{[6-Methyl-3-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine; MSm/z (M + H+) 495 7121-(1-{[6-Methyl-3-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine; MSm/z (M + H+) 495 10981-(1-{[6-Phenyl-3-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine; MSm/z (M + H+) 557 10951-(1-{[6-Phenyl-3-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine; MSm/z (M + H+) 557 570 1-{1-[(3-Methyl-5-phenyl-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine; MS m/z (M + H+)496 510 1-(1-{[6-Methyl-3-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine; MS m/z (M + H+)488

Example 66

A. Methyl 4-thiomorpholinoquinazoline-7-carboxylate, 66c

A solution of methyl 4-chloroquinazoline-7-carboxylate 66a (1.01 mmol,225 mg) and thiomorpholine 66b (2.02 mmol, 208 mg) in MeOH (1.6 mL) wasrefluxed overnight. Compound 66c (30 mg) was isolated afterpurification.

B. 4-Thiomorpholinoquinazoline-7-carboxylic acid, 66d

The title compound 66d was prepared using the method described inExample 29, substituting 66c for 29c in Step B.

C.7-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4-thiomorpholin-4-ylquinazoline,Cpd 951

The title compound Cpd 951 was prepared using the method described inExample 9, substituting 66d for 9c in Step D. MS m/z (M+H⁺) 510.

Example 67

A. 1-(5-Chloro-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone, 67c

To a solution of LDA (2.0 M in THF/heptane/ethylbenzene, 25.3 mmol, 12.6mL) in dry THF was slowly added 1-fluoro-4-chloro-benzene 67a (23.0mmol, 2.45 mL) at −78° C. The mixture was stirred for 1 h at −78° C. andethyl trifluoroacetate 67b (25.3 mmol, 3.02 mL) was added. The reactionmixture was allowed to warm to room temperature overnight and wasquenched with saturated aqueous NH₄C1 solution. The mixture wasextracted with EtOAc. The organic extracts were concentrated andpurified by flash column chromatography (silica gel, 15% EtOAc/hexanes)to give a mixture of the compound 67c along with a regio-isomericby-product, 1-(5-fluoro-2-chloro-phenyl)-2,2,2-trifluoro-ethanone, in aratio of 5:1 (67c is the major product).

B. Methyl 5-chloro-3-(trifluoromethyl)benzo[b]thiophene-2-carboxylate,67e

A solution of compound 67c (6.62 mmol, 1.5 g), methyl 2-mercaptoacetate67d (6.62 mmol, 0.6 mL), and Et₃N (8.6 mmol, 1.2 mL) in acetonitrile (12mL) was heated at 75° C. for 4 h. The reaction was diluted with EtOAcand water. The organic layer was concentrated and purified by flashcolumn chromatography (silica gel, 10% EtOAc/hexanes) to provide thecompound 67e.

C. 5-Chloro-3-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid, 67f

The title compound 67f was prepared using the method described inExample 29, substituting 67e for 29c in Step B.

D. 5-Chloro-3-trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride, 67g

The title compound 65e was prepared using the method described inExample 10, substituting 67f for 10a in Step A.

E.1-(1-{[5-Chloro-3-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine

The title compound Cpd 896 was prepared using the method described inExample 10, substituting 67g for 10b in Step B. MS m/z (M+H⁺) 515.

Following the procedure described above for Example 67 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 6731-(1-{[5-Chloro-3-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 515 5061-(1-{[5-Chloro-3-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺)508

Example 67a

F. 1-(4-Chloro-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone, 67i

To a solution of n-BuLi (1.6 M in hexanes, 4.68 mmol, 2.93 mL) in dryTHF was slowly added 4-chloro-2-fluoro-1-iodo-benzene 67h (3.9 mmol, 1.0g) at −78° C. under N₂. The mixture was stirred for 1 h at −78° C. andethyl trifluoroacetate 67b (0.51 mL, 4.29 mmol) was added. The reactionwas allowed to warm to room temperature overnight and was quenched withsaturated aqueous NH₄Cl solution. The mixture was extracted with EtOAc.The organic extracts were concentrated and purified by flash columnchromatography (silica gel, 15% EtOAc/hexanes) to give compound 67i.

G. Methyl 6-chloro-3-(trifluoromethyl)benzo[b]thiophene-2-carboxylate,67j

The title compound 67j was prepared using a similar method described inExample 67, substituting 67i for 67c in Step B.

Following the procedure described above for Example 67, Steps C-E, andsubstituting the appropriate reagents, starting materials andpurification methods known to those skilled in the art, the followingcompounds of the present invention were prepared:

Cpd Cpd Name and Data 6641-(1-{[6-Chloro-3-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MSm/z (M + H⁺) 515 6991-(1-{[6-Chloro-3-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 515 5121-(1-{[6-Chloro-3-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺)508

Example 67b

H. Methyl 6-chloro-3-(trifluoromethyl)benzo[b]thiophene-2-carboxylate,67l

The title compound 671 was prepared using a similar method described inExample 67, substituting 67k for 67c, substituting NaH for Et₃N, andsubstituting THF and DMSO for CH₃CN in Step B.

Following the procedure described above for Example 67, Steps C-E, andsubstituting the appropriate reagents, starting materials andpurification methods known to those skilled in the art, the followingcompounds of the present invention were prepared:

Cpd Cpd Name and Data 692 1-(Isothiazol-5-ylcarbonyl)-4-(1-{[3-methyl-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (CDCl₃): δ 8.41 (ar, 1H);8.22 (ar, 1H); 7.98 (m, 1H); 7.65 (m, 1H); 7.48, (m, 1H); 3.83 (bm, 5H);3.01 (bm, 4H); 2.5 (s, 3H) MS m/z (M + H⁺) 477.0 5051-(1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺)488 899 1-(1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹HNMR (CDCl₃, 400 MHz): δ 8.11 (s, 1 H), 7.83-7.95 (m, 2 H), 7.65 (d, J =8.6 Hz, 1 H), 7.55 (d, J = 3.1 Hz, 1 H), 3.99-4.67 (m, 6 H), 3.87 (br.s., 2 H), 3.16-3.41 (m, 1 H), 2.66 (s, 3 H), 2.50 (br. s., 4 H). MS m/z(M + H⁺) 495 674 1-(1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹HNMR (CDCl₃, 400 MHz): δ 8.79 (s, 1 H), 8.10 (s, 1 H), 8.03 (s, 1 H),7.89 (d, J = 8 Hz, 1 H), 7.65 (d, J = 8 Hz, 1 H), 3.80-4.40 (m, 8 H),3.28 (m, 1 H), 2.66 (s, 3 H), 2.49 (br. s., 4 H). MS m/z (M + H⁺) 495657 1-(1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1H-pyrrol-2- ylcarbonyl)piperazine ¹H NMR(400 MHz, CDCl₃): δ 8.33 (d, 1H); 8.09 (d, 1H); 7.72 (d, 1H); 6.95 (s,1H); 6.67 (s, 1H); 6.23 (dd, 1H); 4.59 (bm, 3H); 4.26 (m, 1H); 3.40 (m,3H); 2.68 (s, 3H) MS m/z (M + H⁺) 477.1

Example 68

A. Methyl 3-Hydroxy-6-trifluoromethylbenzo[b]thiophene-2-carboxylate,68b

LiOH (4.5 mmol, 0.11 g) was added to a solution of methyl2-fluoro-4-trifluoromethylbenzoate 68a (2.25 mmol, 0.50 g) and methyl2-mercaptoacetate 67d (2.25 mmol, 0.21 mL) in DMF (3 mL) at 0° C. Themixture was stirred at 0° C. for 30 min and then warmed to roomtemperature and stirred for 1 h. Water was added and the resultingsolution was acidified with 1N aqueous HCl. The precipitates werefiltered, washed with water, and dried to give compound 68b.

B. Methyl 3-methoxy-6-trifluoromethylbenzo[b]thiophene-2-carboxylate,68c

A mixture of compound 68b (0.543 mmol, 150 mg), dimethyl sulfate (0.608mmol, 0.058 mL), and sodium bicarbonate (0.57 mmol, 48 mg) in acetonewas heated at reflux overnight. The reaction mixture was cooled andfiltered. The filtrate was concentrated and the residue was partitionedbetween EtOAc and water. The organic solution was concentrated andpurified by flash column chromatography (silica gel, 10% EtOAc/hexanes)to give compound 68c.

C. 3-Methoxy-6-trifluoromethylbenzo[b]thiophene-2-carboxylic acid, 68d

The title compound 68d was prepared using the method described inExample 29, substituting 68c for 29c in Step B.

D. 3-Methoxy-6-trifluoromethylbenzo[b]thiophene-2-carbonyl chloride, 68e

The title compound 68e was prepared using the method described inExample 10, substituting 68d for 10a in Step A.

E.1-(1-{[3-Methoxy-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine,Cpd 649

The title compound Cpd 649 was prepared using the method described inExample 10, substituting 68e for 10b in Step B. ¹H NMR (CDCl₃): δ 8.05(s, 1H), 7.83-7.96 (m, 2H), 7.62 (dd, J=8.4, 1.1 Hz, 1H), 7.55 (d, J=3.2Hz, 1H), 4.55-4.45 (m, 2H), 4.24-4.37 (m, 2H), 4.11-4.24 (m, 2H), 4.07(s, 3H), 3.88 (m, 2H), 3.29 (m, 1H), 2.50 (m, 4H). MS m/z (M+H⁺) 511.

Following the procedure described above for Example 68 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 7001-(1-{[3-Methoxy-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MSm/z (M + H⁺) 511

Example 68a

Following the procedure described above for Example 2 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 7051-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}-4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3- yl]piperazine MSm/z (M + H⁺) 495.1 7041-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}-4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3- yl]piperazine MSm/z (M + H⁺) 495.1

Example 69

A. Methyl 3-fluoro-1H-indole-6-carboxylate, 69a

A solution of methyl 1H-indole-6-carboxylate 1j (11.4 mmol, 2.0 g) andN-fluoro-2,4,6-trimethylpyridinium triflate (14.8 mmol, 4.3 g) in MeOH(100 mL) was heated at reflux for 18 h. The reaction mixture wasconcentrated and purified by flash column chromatography (silica gel,15-20% EtOAc/hexanes) to give compound 69a as an off-white solid.

B. Methyl 3-fluoro-1-(4-fluorophenyl)-1H-indole-6-carboxylate, 69c

Compound 69a (0.264 mmol, 51 mg), CuI (0.0264 mmol, 5 mg) and K₃PO₄(0.66 mmol, 40 mg) were combined in a sealed reaction tube and the vialwas back-flushed with N₂. 4-fluoro-iodobenzene 69b (0.264 mmol, 0.0394mL) and N,N′-dimethylcyclohexane-1,2-diamine (0.0792 mmol, 0.0125 mL)were added via sringe, followed by toluene. The reaction mixture washeated at 95° C. for 6 h. The reaction was diluted with EtOAc and water.The reaction mixture was concentrated and purified by flash columnchromatography (silica gel, 20% EtOAc/hexanes) to give compound 69c.

C. 3-Fluoro-1-(4-fluorophenyl)-1H-indole-6-carboxylic acid, 69d

The title compound 69d was prepared using the method described inExample 29, substituting 69c for 29c in Step B.

D.3-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole,Cpd 574

The title compound Cpd 574 was prepared using the method described inExample 9, substituting 69d for 9c and substituting 2c for 5e in Step D.MS m/z (M+H⁺) 501.

Following the procedure described above for Example 69, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 5893-Fluoro-1-phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 490

Example 70

A. Methyl 4-fluoro-1-triisopropylsilanyl-1H-indole-5-carboxylate, 70b

To a solution of 4-fluoro-1-triisopropylsilanyl-1H-indole-5-carboxylicacid 70a (prepared using a procedure described in Eur. J. Org. Chem.2006, 2956) (8.08 mmol, 2.71 g) in dry CH₂Cl₂ (20 mL) was added oxalylchloride (9.69 mmol, 0.82 mL) followed by DMF (0.81 mmol, 0.063 mL). Thereaction was stirred at rt for 30 min and then concentrated. The residuewas dissolved in CH₂Cl₂ (20 mL) and cooled to 0° C. Et₃N (40.4 mmol, 5.6mL) was added, followed by slow addition of MeOH. The reaction mixturewas stirred at 0° C. for 30 min and concentrated. The residue waspartitioned between EtOAc and water. The organic layer was concentratedand purified by flash column chromatography (silica gel, 5%EtOAc/hexanes) to give compound 70b.

B. Methyl 4-fluoro-1H-indole-5-carboxylate, 70c

TBAF (1M solution in THF, 15.8 mmol, 15.8 mL) was added to a solution ofcompound 70b (7.9 mmol, 2.76 g) in THF at 0° C. After 10 min at roomtemperature, the reaction was diluted with EtOAc and washed with brine,saturated NaHCO₃, and water. The organic layer was concentrated andpurified by flash column chromatography (silica gel, 35% EtOAc/hexanes)to afford compound 70c.

C. Methyl 4-fluoro-1-(4-fluorophenyl)-1H-indole-5-carboxylate, 70d

The title compound 70d was prepared using the method described inExample 69, substituting 70c for 69a in Step B.

D. 4-Fluoro-1-(4-fluoro-phenyl)-1H-indole-5-carboxylic acid, 70e

The title compound 70e was prepared using the method described inExample 29, substituting 70d for 29c in Step B.

E.4-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole,Cpd 1348

The title compound Cpd 1348 was prepared using the method described inExample 9, substituting 70e for 9c in Step D. ¹H NMR (CDCl₃): δ 7.87 (d,J=3.2 Hz, 1H), 7.54 (d, J=3.2 Hz, 1H), 7.36-7.47 (m, 3H), 7.30 (d, J=3.2Hz, 1H), 7.19-7.27 (m, 3H), 6.81 (d, J=3.2 Hz, 1H), 4.52-4.43 (m, 2H),4.28 (dd, J=9.9, 7.7 Hz, 1H), 4.16-4.24 (m, 1H), 4.05-4.16 (m, 2H),3.75-3.95 (m, 2H), 3.27 (m, 1H), 2.38-2.58 (m, 4H). MS m/z (M+H⁺) 508.

Following the procedure described above for Example 70, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following intermediate compoundwas prepared:

Following the procedure described above for Example 70 and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 10696-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 508 1349 6-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 508 631 6-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)- 1H-indole MS m/z(M + H⁺) 501 632 4-Fluoro-1-phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 501

Example 70a

F. 7-Fluoro-1H-indole-5-carboxylic acid, 70h

To a solution of 5-bromo-7-fluoroindole 70f (1.71 mmol, 365 mg) in THFat −60° C. was added n-BuLi (1.6 M solution in hexanes, 5.2 mmol, 3.2mL). The solution was kept at −60° C. for 4 h and was then poured ontoan excess of freshly crushed dry ice. Water was added and the mixturewas acidified to pH=4. The organic phase was concentrated and theresidue was purified by flash column chromatography (silica gel, 35%EtOAc/hexanes) to give compound 70h.

Following the procedure described above for Example 70 and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following intermediate compoundwas prepared:

Following the procedure described above for Example 70 and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 13507-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR(CDCl₃): δ 7.88 (d, J = 3.2 Hz, 1H), 7.76 (d, J = 1.2 Hz, 1H), 7.55 (d,J = 3.2 Hz, 1H), 7.42 (m, 2H), 7.22-7.31 (m, 2H), 7.12-7.22 (m, 2H),6.69-6.81 (m, 1H), 4.53-4.27 (m, 5H), 4.12 (m, 1H), 3.89-3.83 (m, 2H),3.26 (m, 1H), 2.50 (m, 4H) MS m/z (M + H⁺) 508 11117-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 508

Example 70b

G. Methyl 7-methyl-1H-indole-5-carboxylate, 70k

The titled compound was prepared using the method described in Example65, substituting 70i for 65a and substituting 70j for 65b in Step A.

Following the procedure described above for Example 70 and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following intermediate compoundwas prepared:

Following the procedure described above for Example 70 and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 13551-(4-Fluorophenyl)-7-methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR(CDCl₃): δ 7.88 (d, J = 2.4 Hz, 1H), 7.81 (s, 1H), 7.54 (d, J = 2.4 Hz,1H), 7.36 (m, 2H), 7.28 (S, 1H), 7.10-7.21 (m, 3H), 6.67 (d, J = 2.4 Hz,1H), 4.55-4.26 (m, 5H), 4.12 (m, 1H), 3.89 (m, 2H), 3.25 (m, 1H), 2.50(m, 4H), 2.02 (s, 3H) MS m/z (M + H⁺) 504 10761-(4-Fluorophenyl)-7-methyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 504

Example 70c

H. Methyl 4-amino-2-chloro-benzoate, 70m

Acetyl chloride (35.2 mmol, 2.5 mL) was added dropwise to a stirringsolution of 4-amino-2-chloro-benzoic acid 70l (12.9 mmol, 2.22 g) inmethanol (50 mL). The mixture was heated at reflux for 18 h, cooled, andconcentrated under vacuum. The residue was taken up in EtOAc, washedwith saturated aqueous NaHCO₃ and brine, dried, and concentrated undervacuum. The crude product was purified by flash column chromatography(silica gel, 30% EtOAc/hexanes) to give compound 70m.

I. Methyl 4-amino-2-chloro-5-iodo-benzoate, 70n

To a suspension of compound 70m (1.18 g, 6.38 mmol) and CaCO₃ (12.8mmol, 1.28 g) in MeOH (13 mL) was added a solution of iodine monchloride(6.70 mmol, 1.09 g) in CH₂Cl₂ (6 mL) dropwise at room temperature. Theresulting reaction mixture was stirred at room temperature for 1.5 h.The reaction mixture was concentrated and then partitioned between EtOAcand water. The organic layer was concentrated and purified by flashcolumn chromatography (silica gel, 20-25% EtOAc/hexanes) to providemethyl 4-amino-2-chloro-5-iodo-benzoate 70n as major the product andmethyl 4-amino-2-chloro-3-iodo-benzoate 70o as the minor product.

J. Methyl 4-amino-2-chloro-5-((trimethylsilyl)ethynyl)benzoate, 70p

To a mixture of compound 70n (0.642 mmol, 200 mg), CuI (0.064 mmol, 12.2mg) and Pd(PPh₃)₂Cl₂ (0.064 mmol, 45 mg) in THF (2 mL) was addedethynyltrimethylsilane (0.963 mmol, 95 mg) followed by Et₃N (7.19 mmol,1 mL) under N₂. The reaction mixture was stirred at room temperature for1.5 h and then partitioned between EtOAc and water. The organic layerwas concentrated and purified by flash column chromatography (silicagel, 15% EtOAc/hexanes) to give compound 70p.

K. Methyl 6-chloro-1H-indole-5-carboxylate, 70q

A mixture of compound 70p (0.532 mmol, 150 mg) and CuI (0.32 mmol, 60mg) in DMF (1.5 mL) was heated at 110° C. for 5 h and them cooled toroom temperature. The reaction was quenched with water and extractedwith EtOAc. The organic layer was concentrated and purified by flashcolumn chromatography (silica gel, 15% EtOAc/hexanes) to give compound70q.

Following the procedure described above for Example 70c and Example 70and substituting the appropriate reagents, starting materials, andpurification methods known to those skilled in the art, the followingintermediate compounds were prepared:

Following the procedure described above for Example 70 and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 14166-Chloro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 525 1415 1-(4-Fluorophenyl)-6-methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M +H⁺) 504 1414 4-Chloro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR(CDCl₃): δ 7.87 (d, J = 3.2 Hz, 1H), 7.54 (d, J = 3.2 Hz, 1H), 7.40-7.46(m, 2H), 7.34-7.39 (m, 2H), 7.19-7.29 (m, 3H), 6.83 (d, J = 3.2 Hz, 1H),4.52 (m, 1H), 4.35-4.48 (m, 1H), 4.30 (dd, J = 9.9, 7.5 Hz, 1H),4.08-4.18 (m, 1H), 3.75-4.05 (m, 4H), 3.23-3.33 (m, 1H), 2.37-2.57 (m,4H) MS m/z (M + H⁺) 525.

Example 71

A. Methyl 1-(2,2-difluoroethyl)-1H-indole-5-carboxylate, 71b

To a suspension of NaH (60% dispersion in mineral oil, 1.48 mmol, 59 mg)in DMF (2 mL) was slowly added a solution of 1H-indole-5-carboxylic acidmethyl ester 1j (1.14 mmol, 200 mg) in DMF (1 mL) at 0° C. The resultingsolution was stirred at 0° C. for 20 min and 1,1-difluoro-2-iodoethane71a (1.37 mmol, 263 mg) was added. The reaction was warmed to roomtemperature and stirred for 2 h. The reaction was quenched with waterand extracted with EtOAc. The organic layer was concentrated andpurified by flash column chromatography (silica gel, 20% EtOAc/hexanes)to afford compound 71b.

B. 1-(2,2-Difluoroethyl)-1H-indole-5-carboxylic acid, 71c

The title compound 71c was prepared using the method described inExample 29, substituting 71b for 29c in Step B.

C.1-(2,2-Difluoroethyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole,Cpd 711

The title compound Cpd 711 was prepared using the method described inExample 9, substituting 71c for 9c in Step D. ¹H NMR (CDCl₃): δ 7.94 (s,1H), 7.88 (d, J=2.9 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.54 (d, J=2.9 Hz,1H), 7.36 (d, J=8.6 Hz, 1H), 7.17 (d, J=2.9 Hz, 1H), 6.63 (d, J=2.9 Hz,1H), 6.01 (m, 1H), 4.51-4.24 (m, 7H), 4.12 (m, 1H), 3.85 (m, 2H), 3.24(m, 1H), 2.49 (m, 4H). MS m/z (M+H⁺) 460.

Following the procedure described above for Example 71, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Following the procedure described above for Example 71, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 813 1-(2,2-Difluoroethyl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 460 1031 N-Methyl-N-phenyl-2-[5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]acetamide MS m/z (M + H⁺) 543 1032N-Methyl-N-phenyl-2-[5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]acetamide MS m/z (M + H⁺) 543 10351-(2-Oxo-2-pyrrolidin-1-ylethyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 507 1046 1-(Pyridin-4-ylmethyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 487 1047 1-(Pyridin-4-ylmethyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 487 1048 1-(Pyridin-3-ylmethyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M +H⁺) 487

Example 72

A. Ethyl 1-(4-fluorobenzyl)-1H-indazole-5-carboxylate, 72c, and ethyl2-(4-fluorobenzyl)-2H-indazole-5-carboxylate, 72d

Ethyl 1H-indazole-5-carboxylate 72a (0.79 mmol, 150 mg) and Cs₂CO₃ (0.96mmol, 312 mg) were combined in 2 mL of DMF, producing a clear, red-brownsolution. Neat 1-(bromomethyl)-4-fluorobenzene 72b (0.87 mmol, 0.11 mL)was added dropwise and the mixture was stirred at room temperatureovernight. EtOAc was added and the organic layer was washed with waterand brine. The organic solution was dried over Na₂SO₄ and concentratedto give 260 mg of orange solid. The crude product was purified by flashcolumn chromatography (silica gel, 15-50% EtOAc/heptanes) to give 133 mg(57%) of compound 72c as an orange solid and 67 mg (28%) of compound 72das a white solid.

Compound 72c:

¹H NMR (400 MHz, CDCl₃): δ 1.41 (t, J=7.1 Hz, 3H), 4.40 (q, J=7.1 Hz,2H), 5.58 (s, 2H), 6.99 (t, J=8.7 Hz, 2H), 7.19 (dd, J=8.8, 5.3 Hz, 2H),7.36 (dt, J=8.9, 0.8 Hz, 1H), 8.04 (dd, J=8.9, 1.5 Hz, 1H), 8.15 (d,J=0.9 Hz, 1H), 8.53 (dd, J=1.5, 0.8 Hz, 1H). MS m/z (M+H⁺) 299.1.

Compound 72d:

¹H NMR (400 MHz, CDCl₃): δ 1.41 (t, J=7.1 Hz, 3H), 4.39 (q, J=7.1 Hz,2H), 5.59 (s, 2H), 7.07 (t, J=8.7 Hz, 2H), 7.27-7.34 (m, 2H), 7.72 (dt,J=9.1, 0.9 Hz, 1H), 7.92 (dd, J=9.1, 1.6 Hz, 1H), 8.02-8.06 (m, 1H),8.48 (dd, J=1.5, 0.9 Hz, 1H). MS m/z (M+H⁺) 299.1.

B. 1-(4-Fluorobenzyl)-1H-indazole-5-carboxylate, 72e

To a stirring solution of compound 72c (0.43 mmol, 128 mg) in 2.5 mL ofTHF and 0.5 mL of MeOH was added 3N aqueous NaOH (2.62 mmol, 0.87 mL)and 0.5 mL of water. After stirring at room temperature overnight, themixture was concentrated under vacuum. The yellow residue was dissolvedin 10 mL of water and acidified to pH 2-3 with aqueous HCl. Theresulting precipitate was vacuum-filtered through a paper disc andwashed with water. The remaining material was pumped at high vacuum togive 108 mg (93%) of compound 72e as a pale yellow solid. ¹H NMR (400MHz, CDCl₃): δ 1.41 (t, J=7.1 Hz, 3H), 4.39 (q, J=7.1 Hz, 2H), 5.59 (s,2H), 7.07 (t, J=8.7 Hz, 2H), 7.27-7.34 (m, 2H), 7.72 (dt, J=9.1, 0.9 Hz,1H), 7.92 (dd, J=9.1, 1.6 Hz, 1H), 8.02-8.06 (m, 1H), 8.48 (dd, J=1.5,0.9 Hz, 1H). MS m/z (M+H⁺) 271.2.

C.1-(4-Fluorobenzyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indazole,Cpd 1029

The title compound Cpd 1029 was prepared using the method described inExample 9, substituting 72e for 9c and substituting HBTU for HATU inStep D. ¹H NMR (400 MHz, CDCl₃): δ 1.41 (t, J=7.1 Hz, 3H), 4.39 (q,J=7.1 Hz, 2H), 5.59 (s, 2H), 7.07 (t, J=8.7 Hz, 2H), 7.27-7.34 (m, 2H),7.72 (dt, J=9.1, 0.9 Hz, 1H), 7.92 (dd, J=9.1, 1.6 Hz, 1H), 8.02-8.06(m, 1H), 8.48 (dd, J=1.5, 0.9 Hz, 1H). MS m/z (M+H⁺) 505.2.

Following the procedure described above for Example 72, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following intermediate compoundswere prepared:

Following the procedure described above for Example 72, and substitutingthe appropriate reagents, starting materials, and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Cpd Cpd Name and Data 1030 2-(4-Fluorobenzyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2H- indazole ¹H NMR(400 MHz, CD₃OD): δ 3.19-3.30 (m, 4 H), 4.05 (d, J = 5.6 Hz, 3 H),4.25-4.88 (m, 6 H), 5.66 (s, 2 H), 7.09 (t, J = 8.4 Hz, 2 H), 7.33-7.43(m, 2 H), 7.57 (d, J = 9.0 Hz, 1 H), 7.69 (d, J = 9.0 Hz, 1 H), 7.88 (m,J = 2.9 Hz, 1 H), 7.97 (d, J = 2.7 Hz, 1 H), 8.12 (s, 1 H), 8.49 (s, 1H) MS m/z (M + H⁺) 505.2 10365-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)benzyl]- 1H-indazole ¹HNMR (400 MHz, CD₃OD): δ 3.24 (br. s., 4 H), 3.89-4.12 (m, 3 H),4.25-4.85 (m, 6 H), 5.78 (s, 2 H), 7.37 (m, J = 8.1 Hz, 2 H), 7.60 (m, J= 8.1 Hz, 2 H), 7.66 (d, J = 8.8 Hz, 1 H), 7.72 (dd, J = 8.8, 1.5 Hz, 1H), 7.88 (d, J = 3.0 Hz, 1 H), 7.97 (d, J = 3.3 Hz, 1 H), 8.18 (s, 1 H),8.23 (s, 1 H) MS m/z (M + H⁺) 555.2 10375-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-[4-(trifluoromethyl)benzyl]- 2H-indazole ¹HNMR (400 MHz, CD₃OD): δ 3.18-3.41 (m, 4 H), 3.92-4.18 (m, 3 H),4.27-4.86 (m, 6 H), 5.79 (s, 2 H), 7.47 (d, J = 8.1 Hz, 2 H), 7.58 (dd,J = 9.1, 1.5 Hz, 1 H), 7.66 (d, J = 8.1 Hz, 2 H), 7.70 (d, 1 H), 7.88(d, J = 3.0 Hz, 1 H), 7.97 (d, J = 3.0 Hz, 1 H), 8.14 (s, 1 H), 8.56 (s,1 H) MS m/z (M + H⁺) 555.2 10385-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1-[3-(trifluoromethyl)benzyl]- 1H-indazole ¹HNMR (400 MHz, CD₃OD): δ 3.25 (br. s., 4 H), 3.89-4.13 (m, 3 H),4.22-4.82 (m, 6 H), 5.78 (s, 2 H), 7.40-7.54 (m, 3 H), 7.58 (m, J = 7.3Hz, 1 H), 7.69 (m, J = 8.6 Hz, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.88 (d,J = 3.3 Hz, 1 H), 7.97 (d, J = 3.3 Hz, 1 H), 8.18 (s, 1 H), 8.24 (s, 1H) MS m/z (M + H⁺) 555.2 10395-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2-[3-(trifluoromethyl)benzyl]- 2H-indazole ¹HNMR (400 MHz, CD₃OD): δ 3.30 (br. s., 4 H), 4.04 (d, J = 6.8 Hz, 3 H),4.29-4.84 (m, 6 H), 5.78 (s, 2 H), 7.58 (t, J = 7.1 Hz, 3 H), 7.64 (br.s., 2 H), 7.70 (d, J = 9.1 Hz, 1 H), 7.88 (d, J = 3.0 Hz, 1 H), 7.97 (d,J = 3.0 Hz, 1 H), 8.14 (s, 1 H), 8.56 (s, 1 H) MS m/z (M + H⁺) 555.21411 1-(1-Phenylethyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole ¹H NMR(400 MHz, acetone-d₆): δ 2.01 (d, J = 7.1 Hz, 3 H), 3.35 (br. s., 4 H),4.07 (br. s., 2 H), 4.11-4.19 (m, 1 H), 4.25-4.53 (m, 2 H), 6 4.60 (br.s., 1 H), 4.68-4.96 (m, 3 H), 6.07 (q, J = 7.1 Hz, 1 H), 7.24 (d, J =7.1 Hz, 1 H), 7.30 (t, J = 7.3 Hz, 2 H), 7.33-7.39 (m, 2 H), 7.58-7.68(m, 2 H), 7.92 (d, J = 3.3 Hz, 1 H), 7.98 (d, J = 3.0 Hz, 1 H), 8.12 (s,1 H), 8.18 (s, 1 H) MS m/z (M + H⁺) 501.1 10402-(1-Phenylethyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2H- indazole ¹H NMR(400 MHz, CD₃OD): δ 2.04 (d, J = 7.1 Hz, 3 H), 3.20 (br. s., 4 H),3.91-4.05 (m, 3 H), 4.25-4.63 (m, 4 H), 4.72 (br. s., 2 4 H), 5.94 (q, J= 6.9 Hz, 1 H), 7.25-7.39 (m, 5 H), 7.57 (dd, J = 9.0, 1.4 Hz, 1 H),7.69 (d, J = 9.1 Hz, 1 H), 7.88 (d, J = 3.0 Hz, 1 H), 7.97 (d, J = 3.3Hz, 1 H), 8.12 (s, 1 H), 8.51 (s, 1 H) MS m/z (M + H⁺) 501.3 10431-(4-Fluorobenzyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-pyrrolo[2,3-b]pyridine ¹H NMR (400 MHz, CDCl₃): δ 3.49 (br. s., 4 H),4.12 (br. s., 2 H), 4.23-4.33 (m, 1 H), 4.34-5.17 (m, 6 H), 5.56 (s, 2H), 6.61 (d, J = 3.5 Hz, 1 H), 7.08 (t, J = 8.7 Hz, 2 H), 7.38 (dd, J =8.6, 5.6 Hz, 2 H), 7.63 (d, J = 3.5 Hz, 1 H), 7.93 (d, J = 3.3 Hz, 1 H),7.99 (d, J = 3.3 Hz, 1 H), 8.27 (d, J = 1.8 Hz, 1 H), 8.61 (d, J = 1.8Hz, 1 H) MS m/z (M + H⁺) 505.2 10491-[2-(4-Fluorophenyl)ethyl]-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole ¹H NMR(400 MHz, acetone-d₆): δ 3.24 (t, J = 7.2 Hz, 2 H), 3.40 (br. s., 4 H),4.09 (br. s., 2 H), 4.16-4.23 (m, 1 H), 4.31-4.65 (m, 4 H), 6 4.69 (t, J= 7.2 Hz, 2 H), 4.85 (br. s., 2 H), 6.96 (t, J = 8.8 Hz, 2 H), 7.19 (dd,J = 8.3, 5.6 Hz, 2 H), 7.49 (d, J = 8.8 Hz, 1 H), 7.62 (dd, J = 8.8, 1.3Hz, 1 H), 7.93 (d, J = 3.0 Hz, 1 H), 8.00 (d, J = 3.0 Hz, 1 H), 8.09 (s,1 H), 8.12 (s, 1 H) MS m/z (M + H⁺) 519.2 10502-[2-(4-Fluorophenyl)ethyl]-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2H- indazole ¹H NMR(400 MHz, acetone-d₆): δ 3.35 (t, J = 7.1 Hz, 2 H), 3.38-3.43 (m, 4 H),4.09 (br. s., 2 H), 4.12-4.20 (m, 1 H), 4.31-4.69 (m, 4 6 H), 4.74 (t, J= 7.2 Hz, 2 H), 4.84 (br. s., 2 H), 7.01 (t, J = 8.7 Hz, 2 H), 7.21 (dd,J = 8.3, 5.6 Hz, 2 H), 7.55 (dd, J = 9.1, 1.5 Hz, 1 H), 7.66 (d, J = 9.1Hz, 1 H), 7.93 (d, J = 3.0 Hz, 1 H), 8.00 (d, J = 3.3 Hz, 1 H), 8.03 (s,1 H), 8.23 (s, 1 H) MS m/z (M + H⁺) 519.2 10511-(4-Fluorobenzyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole ¹H NMR(400 MHz, acetone-d₆): δ 3.14-3.23 (m, 4 H), 3.91-4.00 (m, 1 H),4.01-4.12 (m, 2 H), 4.26-4.56 (m, 3 H), 4.57-4.92 (m, 3 6 H), 5.74 (s, 2H), 7.09 (t, J = 8.8 Hz, 2 H), 7.37-7.46 (m, 3 H), 7.84 (d, J = 8.3 Hz,1 H), 7.89-7.95 (m, 2 H), 7.99 (d, J = 3.0 Hz, 1 H), 8.12 (s, 1 H) MSm/z (M + H⁺) 505.2 1052 2-(4-Fluorobenzyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2H- indazole ¹H NMR(400 MHz, acetone-d₆): δ 3.21-3.30 (m, 4 H), 3.94-4.15 (m, 3 H),4.28-4.52 (m, 2 H), 4.52-4.68 (m, 1 H), 4.68-4.93 (m, 3 6 H), 5.72 (s, 2H), 7.15 (t, J = 8.8 Hz, 2 H), 7.34 (dd, J = 8.6, 1.3 Hz, 1 H),7.45-7.52 (m, 2 H), 7.75 (d, J = 8.6 Hz, 1 H), 7.91 (s, 1 H), 7.92 (d, J= 3.3 Hz, 1 H), 7.99 (d, J = 3.3 Hz, 1 H), 8.42 (s, 1 H) MS m/z (M + H⁺)505.2

Example 72a

D. Methyl 1-(4-cyanobenzyl)-1H-indazole-5-carboxylate, 72f

The title compound 72f was prepared using the procedure described inExample 72, substituting methyl 1H-indazole-5-carboxylate for 72a andsubstituting 4-(bromomethyl)benzonitrile for 72b. ¹H NMR (400 MHz,CDCl₃): δ 3.95 (s, 3H), 5.67 (s, 2H), 7.26 (d, J=8.2 Hz, 2H), 7.33 (d,J=8.9 Hz, 1H), 7.61 (d, J=8.3 Hz, 2H), 8.06 (dd, J=8.9, 1.4 Hz, 1H),8.18 (s, 1H), 8.55 (s, 1H). (M+H⁺) 292.2

E. 1-(4-cyanobenzyl)-1H-indazole-5-carboxylic acid, 72g, and1-(4-carbamoylbenzyl)-1H-indazole-5-carboxylic acid, 72h

To a stiffing solution of compound 72f (0.35 mmol, 102 mg) in 2 mL ofTHF and 0.5 mL of MeOH was added 3N aqueous NaOH (2.45 mmol, 0.82 mL).After stiffing at room temperature overnight, the mixture wasconcentrated under vacuum. The yellow residue was dissolved in 15 mL ofwater and acidified to pH 1-2 with aqueous HCl. The resultingprecipitate was vacuum-filtered through a paper disc and washed withwater. The remaining material was pumped at high vacuum to give 87 mg ofa 3:1 mixture (as shown by LC/MS) of compound 72g and compound 72h as anoff-white solid. Compound 72g (less polar): MS m/z (M+H⁺) 278.1.Compound 72h (more polar): MS m/z (M+H⁺) 296.

F.4-{[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indazol-1-yl]methyl}benzonitrile,Cpd 1045, and4-{[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indazol-1-yl]methyl}benzamide,Cpd 1044

The title compounds Cpd 1045 and Cpd 1044 were prepared using the methoddescribed in Example 9, substituting the mixture of 72g and 72h preparedin Step E above for 9c and substituting HBTU for HATU in Step D. Theproducts were separated by preparative reverse phase chromatography togive 64 mg of Cpd 1045 (less polar) and 6.4 mg of Cpd 1044 (more polar).

Cpd 1045:

¹H NMR (400 MHz, acetone-d₆): δ 3.24-3.49 (m, 4H), 4.00-4.11 (m, 2H),4.11-4.20 (m, 1H), 4.26-4.96 (m, 6H), 5.85 (s, 2H), 7.45 (d, J=8.3 Hz,2H), 7.66-7.72 (m, 2H), 7.74 (d, J=8.3 Hz, 2H), 7.92 (d, J=3.3 Hz, 1H),7.99 (d, J=3.0 Hz, 1H), 8.16 (s, 1H), 8.20 (s, 1H)

Cpd 1044:

¹H NMR (400 MHz, acetone-d₆): δ 3.14 (br. s., 4H), 3.87-3.96 (m, 1H),3.96-4.08 (m, 2H), 4.35 (br. s., 2H), 4.47-4.85 (m, 4H), 5.78 (s, 2H),7.35 (d, J=8.3 Hz, 2H), 7.66 (s, J=8.8 Hz, 1H), 7.70 (d, J=8.6, 1.5 Hz,1H), 7.88 (d, J=8.1 Hz, 2H), 7.91 (d, J=3.3 Hz, 1H), 7.98 (d, J=3.3 Hz,1H), 8.16 (s, 1H), 8.18 (s, 1H)

BIOLOGICAL EXAMPLES In Vitro Methods Example 1 MGL Enzyme Activity Assay

All rate-based assays were performed in black 384-well polypropylenepolymerase chain reaction (“PCR”) microplates (Abgene) in a total volumeof 30 μL. Substrate 4-methylumbelliferyl butyrate (4MU-B; Sigma) andeither purified mutant MGL (mut-MGLL 11-313 L179S L186S) or purifiedwild type MGL (wt-MGLL 6H-11-313) were diluted separately into 20 mM1,4-piperazinediethanesulfonic acid (“PIPES”) buffer (pH=7.0),containing 150 mM NaCl and 0.001% Tween 20. Compounds of Formula (I)were pre-dispensed (50 mL) into the assay plate using a CartesianHummingbird prior to adding 4MU-B (25 μL, of 1.2× solution to a finalconcentration of 10 μM) followed by enzyme (5 μL, of a 6x solution to afinal concentration of 5 nM) to initiate the reaction. Final compoundconcentrations ranged from 17 to 0.0003 μM. The fluorescence change dueto 4MU-B cleavage was monitored with excitation and emission wavelengthsof 335 and 440 nm, respectively, and a bandwidth of 10 nm (Safire²,Tecan) at 37° C. for 5 min

The IC₅₀ values for compounds of Formula (I) were determined using Excelfrom a fit of the equation to the concentration-response plot of thefractional activity as a function of inhibitor concentration.

BIOLOGICAL DATA TABLE 1 Chemistry MGL mutant MGL wild type Cpd Exampleinh IC₅₀ (μM) inh IC₅₀ (μM) 1  1 0.0283 2  1 0.0081 3  1 5.20 4  1 0.7315  1 0.0657 0.523 6  1 0.0080 7  1 0.0346 0.131 8  1 0.101 9  1 0.00870.0174 10  1 0.329 11  1 2.86 12  1 0.0470 13  1 0.0200 0.0192 14  11.22 15  1 2.18 16  1 0.828 17  1 14.3 18  1 0.124 19  1 0.979 20  11.89 21  1 2.35 22  1 4.81 23  1 2.78 24  1 2.45 25  1 2.29 26  1 15.4567  1 0.018 0.015 579  1 0.065 581  1 0.080 587  1 0.014 0.119 595  10.098 0.500 598  1 0.979 1061  1 0.006 1071  1 0.008 1139  1 0.027 1147 1 0.032 1163  1 0.009 0.048 1174  1 <0.005 0.066 1201  1 0.007 0.1511248  1 0.559 1356  1 <0.005 <0.005 1357  1 <0.005 <0.005 1358  1 <0.005<0.005 1359  1 <0.005 <0.005 1360  1 <0.005 <0.005 1361  1 <0.005 1362 1 <0.005 1363  1 <0.005 1364  1 <0.005 1366  1 <0.005 1382  1 0.0691408  1 <0.005 586  1b 0.112 596  1b 0.543 603  1b 1.722 630  1b 0.7141062  1b 0.007 1072  1b 0.008 1073  1b 0.034 1089  1b 0.010 1097  1b0.012 1105  1b 0.013 1107  1b 0.014 1120  1b 0.018 1121  1b 0.018 1126 1b 0.019 1127  1b 0.020 1128  1b 0.021 1134  1b 0.025 1135  1b 0.0251176  1b 0.070 1181  1b 0.077 1189  1b 0.097 1192  1b 0.109 1197  1b0.133 1216  1b 0.216 1219  1b 0.235 1230  1b 0.307 1247  1b 0.539 1263 1b 0.968 1312  1b <0.00500035 1314  1b <0.00500035 1337  1b <0.005000351338  1b <0.00500035 1339  1b <0.00500035 1410  1b 0.089 656  1c 0.0081079  1c 0.009 1184  1c 0.086 1199  1c 0.146 1141  1d 0.010 0.028 1151 1d 0.037 1158  1d 0.042 592  1e 0.078 0.253 1125  1e <0.00500035 0.0191187  1e <0.00500035 0.092 629  1f 0.053 1180  1f 0.075 1313  1f<0.00500035 1409  1g 27  2 14.5 487  1a <0.005 0.0104 28  2 1.63 29  20.363 30  2 0.670 31  2 5.07 32  2 0.761 33  2 0.633 34  2 1.38 35  20.459 36  2 0.115 37  2 0.117 5.99 38  2 0.666 39  2 0.0317 0.0147 40  20.0491 41  2 0.0322 42  2 0.354 43  2 0.0310 1.26 44  2 0.0700 45  23.42 46  2 3.43 47  2 0.129 0.129 48  2 0.551 49  2 5.78 50  2 8.71 51 2 0.227 52  2 1.94 53  2 0.988 54  2 0.223 55  2 0.307 56  2 13.8 57  25.24 58  2 2.63 59  2 3.38 60  2 2.66 461  2 5.28 462  2 5.05 463  29.63 464  2 5.82 465  2 8.27 466  2 10.9 467  2 9.82 468  2 2.70 469  22.25 470  2 7.06 471  2 3.38 472  2 9.73 531  2 0.766 539  2 11.476 541 2 13.059 559  2 1.287 562  2 13.474 565  2 11.392 622  2 1.360 627  213.225 628  2 13.502 954  2 2.743 1266  2 1.083 1284  2 2.292 1404  213.286 1482  2 >16.9981 1483  2 >16.6686 1485  2 >16.6686 1464 2 >16.6686 61  3 0.0385 676  3 <0.005 0.021 703  3 0.014 0.088 716  30.023 0.140 722  3 0.051 0.180 741  3 0.038 0.298 753  3 0.075 0.434 921 3 6.331 1067  3 <0.005 0.007 1166  3 0.052 1235  3 0.030 0.360 1236  30.042 0.390 1242  3 0.146 0.461 1243  3 0.463 1246  3 0.207 0.506 1276 3 0.650 1.764 1283  3 0.063 2.171 1292  3 0.244 3.070 1383  3 0.0811400  3 5.929 1401  3 8.843 1402  3 9.972 62  4 2.95 63  4 4.84 64  42.29 65  4 0.893 66  4 1.40 67  4 0.134 68  4 12.7 69  4 4.31 70  4 4.8371  4 7.58 72  4 0.0270 0.326 73  4 1.54 74  4 3.34 75  4 0.0939 76  42.43 77  4 0.0478 78  4 0.607 79  4 0.125 80  4 4.85 81  4 0.227 82  40.466 83  4 0.0989 474  4 4.68 473  4 9.79 84  4 4.67 85  4 4.17 86  43.92 87  4 4.81 88  4 1.95 89  4 1.76 90  4 14.7 91  4 1.87 92  4 13.693  4 3.93 94  4 1.88 95  4 0.669 96  4 14.0 97  4 0.920 98  4 4.58 99 4 6.36 100  4 3.50 101  4 0.299 102  4 3.04 103  4 8.93 104  4 3.90 105 4 2.97 106  4 0.539 107  4 1.12 108  4 8.63 109  4 0.0385 110  4 1.22111  4 14.0 496  4 1.30 558  4 0.410 618  4 0.140 619  4 0.142 620  40.153 621  4 0.271 623  4 2.423 624  4 4.687 625  4 9.761 626  4 12.74133  5 <0.005 0.0673 134  5 0.0114 135  5 <0.005 136  5 <0.005 137  50.0073 138  5 <0.005 139  5 0.968 140  5 0.653 141  5 0.412 142  5 1.55143  5 7.14 144  5 4.68 145  5 2.69 146  5 0.518 147  5 <0.005 148  5<0.005 <0.005 149  5 0.249 0.0769 150  5 0.0058 <0.005 151  5 0.114 152 5 3.51 153  5 0.355 154  5 0.127 155  5 3.75 156  5 1.54 157  5 0.853158  5 0.0339 0.657 159  5 0.682 160  5 2.54 161  5 0.0050 0.0117 162  5<0.005 163  5 0.0239 164  5 0.0100 165  5 0.451 166  5 <0.005 <0.005 167 5 0.0500 0.0152 168  5 0.0059 <0.005 169  5 5.55 170  5 0.0679 171  50.380 172  5 0.0088 0.0073 475  5 0.234 476  5 0.0443 0.338 477  5 1.38478  5 3.12 479  5 2.82 298  5 1.16 112  5 1.08 113  5 0.587 114  50.840 115  5 0.0180 0.0117 116  5 1.49 117  5 0.396 4.23 489  5 <0.0050.0090 490  5 <0.005 0.0223 485  5 <0.005 0.102 502  5 6.091 503  50.152 517  5 0.073 1.340 523  5 3.135 524  5 4.368 526  5 8.102 610  510.347 611  5 13.253 636  5 0.021 637  5 0.041 638  5 0.189 639  5 0.419640  5 15.944 641  5 <0.005 643  5 0.411 644  5 3.086 646  5 7.158 648 5 0.018 655  5 0.008 658  5 0.009 667  5 0.014 669  5 0.015 672  50.017 675  5 0.019 678  5 0.022 682  5 0.030 687  5 0.044 688  5 0.044693  5 0.047 694  5 0.047 696  5 0.059 698  5 0.065 702  5 0.303 710  50.123 719  5 0.154 721  5 0.173 726  5 0.218 727  5 0.219 728  5 0.231730  5 0.238 731  5 0.238 732  5 0.239 733  5 0.240 735  5 0.268 739  50.290 740  5 0.294 743  5 0.324 744  5 0.335 746  5 0.373 747  5 0.377748  5 0.384 750  5 0.395 751  5 0.402 754  5 0.447 755  5 0.468 756  50.519 758  5 0.535 760  5 0.581 762  5 0.632 763  5 0.635 764  5 0.636766  5 0.680 768  5 0.697 770  5 0.740 772  5 0.799 774  5 0.848 776  50.902 779  5 0.944 781  5 1.042 782  5 1.066 783  5 1.086 785  5 1.190786  5 1.203 787  5 1.209 788  5 1.227 791  5 1.448 792  5 1.458 793  51.460 794  5 1.469 795  5 1.502 796  5 1.529 797  5 1.596 799  5 1.667800  5 1.696 804  5 0.058 1.993 808  5 2.076 809  5 2.104 814  5 2.434815  5 2.492 816  5 2.636 818  5 2.702 821  5 2.847 823  5 2.970 824  53.120 825  5 3.148 826  5 3.287 827  5 3.308 828  5 3.733 830  5 3.942831  5 4.097 835  5 4.705 836  5 4.756 838  5 5.113 839  5 5.135 840  55.155 842  5 5.526 843  5 5.531 844  5 6.104 845  5 6.421 846  5 6.448848  5 6.902 849  5 7.011 850  5 7.278 852  5 8.078 853  5 8.344 854 5 >16.6686 8.414 855  5 8.435 857  5 8.724 859  5 8.815 860  5 8.819862  5 9.510 863  5 10.158 864  5 10.221 865  5 10.287 868  5 12.112 871 5 13.323 873  5 14.703 874  5 15.209 886  5 <0.005 887  5 <0.005 888  5<0.005 889  5 <0.005 890  5 <0.005 891  5 <0.005 892  5 <0.005 893  5<0.005 894  5 <0.005 905  5 0.015 910  5 0.194 912  5 0.472 915  5 0.944923  5 8.756 925  5 9.968 926  5 10.457 946  5 1.001 947  5 1.065 952  50.012 953  5 >16.6686 965  5 0.037 966  5 0.222 993  5 1.514 1000  50.111 1001  5 1.403 1002  5 5.292 1003  5 1.613 1004  5 0.167 1017  50.035 1041  5 0.019 1042  5 5.274 1053  5 0.018 1082  5 0.009 1083  50.009 1103  5 0.013 1119  5 0.017 1122  5 0.018 1123  5 0.019 1146  50.032 1150  5 <0.005 0.036 1156  5 0.041 1164  5 0.048 1179  5 0.0731194  5 0.118 1202  5 0.152 1203  5 0.153 1214  5 0.209 1218  5 0.2221223  5 0.267 1225  5 0.273 1245  5 0.500 1249  5 0.605 1271  5 1.5681272  5 1.608 1287  5 2.450 1293  5 3.172 1297  5 3.311 1298  5 3.8501299  5 3.856 1300  5 4.135 1301  5 4.608 1305  5 6.676 1307  5 8.7761326  5 <0.005 1327  5 <0.005 1328  5 <0.005 1329  5 <0.005 1330  5<0.005 1331  5 <0.005 1332  5 <0.005 1333  5 <0.005 1334  5 <0.005 1378 5 0.009 1379  5 0.022 1381  5 0.065 1384  5 0.092 1385  5 0.152 1386  50.180 1392  5 0.693 1395  5 0.866 1396  5 1.159 1397  5 1.165 1403  512.331 1407  5 <0.005 1412  5 0.087 1442  5 >16.6686 1444  5 >16.66861445  5 >16.6686 1491  5 >16.6686 1460  5 >16.6686 1434  5 >16.6686 1477 5 >16.6686 1432  5 >16.6686 1489  5 >16.6686 >16.6686 1490  5 >16.66861481  5 >16.6686 1436  5 >16.6686 >16.6686 1473  5 >16.6686 1475 5 >16.6686 1446  5 >16.6686 1447  5 >16.6686 1448  5 >16.6686 1449 5 >16.6686 1450  5 >16.6686 1451  5 >16.6686 1452  5 >16.6686 1453 5 >16.6686 173  6 0.532 174  6 0.0062 175  6 <0.005 <0.005 176  6<0.005 177  6 0.0088 178  6 <0.005 179  6 0.0069 180  6 <0.005 181  6<0.005 182  6 <0.005 183  6 <0.005 184  6 0.0385 185  6 2.63 186  60.0068 0.0184 187  6 0.546 188  6 0.0409 189  6 0.651 190  6 2.51 191  61.46 192  6 2.36 193  6 0.460 194  6 0.553 195  6 0.0824 196  6 0.01590.216 197  6 0.931 198  6 0.211 199  6 5.46 200  6 0.168 201  6 1.57 202 6 0.477 203  6 1.05 204  6 0.371 205  6 0.0189 206  6 1.36 207  60.0098 208  6 0.0190 0.0920 209  6 0.0170 210  6 0.0101 211  6 0.0143212  6 <0.005 <0.005 213  6 <0.005 214  6 <0.005 215  6 0.0540 216  60.0113 217  6 0.561 218  6 0.0200 219  6 0.0145 0.0320 220  6 <0.005 221 6 <0.005 222  6 0.242 223  6 0.0164 224  6 <0.005 225  6 0.0523 0.0547226  6 0.0696 227  6 <0.005 0.0070 228  6 0.0204 <0.005 229  6 <0.005<0.005 230  6 0.0116 231  6 0.516 232  6 <0.005 0.0829 233  6 1.78 234 6 0.157 235  6 1.70 236  6 0.499 237  6 <0.005 <0.005 238  6 0.0516 239 6 <0.005 0.0100 240  6 <0.005 0.0508 241  6 0.0070 242  6 <0.005 243  60.0057 244  6 <0.005 245  6 <0.005 0.0164 246  6 0.0200 247  6 <0.005248  6 <0.005 0.0070 249  6 0.0120 250  6 <0.005 <0.005 251  6 <0.0050.0170 252  6 0.0125 0.0808 253  6 <0.005 0.0494 254  6 <0.005 <0.005255  6 0.0102 256  6 0.0110 0.0134 257  6 <0.005 <0.005 258  6 <0.005259  6 0.0060 260  6 0.0089 261  6 <0.005 0.0084 262  6 <0.005 <0.005263  6 <0.005 0.0285 264  6 0.0050 265  6 <0.005 0.0190 266  6 <0.0050.0498 267  6 <0.005 268  6 0.0544 488  6 0.0173 0.382 1070  6 <0.0050.008 1102  6 <0.005 0.013 269  7 0.215 270  7 0.289 271  7 0.210 272  72.71 273  7 0.0872 274  7 0.0705 275  7 1.07 276  7 0.341 277  7 4.70278  7 4.18 279  7 0.640 280  7 0.141 281  7 0.0930 282  7 <0.005 283  70.0222 284  7 4.88 285  7 13.2 286  7 0.150 287  7 6.81 288  7 3.54 289 7 6.56 290  7 0.0600 291  7 0.0071 292  7 2.59 293  7 0.380 294  70.638 295  7 2.13 296  7 1.04 297  7 0.358 299  8 0.683 300  8 6.99 301 8 0.326 302  8 0.143 303  8 0.314 0.173 304  8 0.358 305  8 0.132 306 8 0.666 307  8 0.408 308  8 6.07 309  8 1.17 310  8 0.0842 311  80.0640 312  8 0.0065 480  8 3.38 1057  8 0.006 1078  8 0.009 1085  80.009 1087  8 0.009 1094  8 0.011 1112  8 0.016 1118  8 0.016 1140  80.027 1143  8 0.030 1145  8 0.031 1169  8 0.055 1217  8 0.220 1222  80.266 1232  8 0.326 1256  8 0.808 1258  8 0.829 1262  8 0.950 1269  81.264 1308  8 9.277 1310  8 11.649 1324  8 <0.005 1325  8 <0.005 1335  8<0.005 1336  8 <0.005 1398  8 1.222 1423  8 0.278 1424  8 0.075 1425  80.009 1426  8 <0.005 1427  8 0.006 1428  8 0.014 1429  8 0.036 186-A  80.010 567-A  8 0.028 1478  8 >16.6686 1465  8 >16.6686 313  9 <0.005 314 9 0.0100 <0.005 315  9 5.00 316  9 <0.005 <0.005 317  9 0.0050 <0.005318  9 <0.005 0.0139 319  9 0.0088 320  9 8.53 321  9 0.0378 322  9 13.7606  9 2.038 647  9 12.723 654  9 0.007 681  9 0.027 713  9 0.135 718  90.148 723  9 0.181 745  9 0.342 767  9 0.691 775  9 0.862 806  9 2.052812  9 2.192 817  9 2.700 820  9 2.815 822  9 2.856 829  9 3.905 832  94.239 856  9 8.486 918  9 2.891 1054  9 0.005 1055  9 0.005 1056  90.006 1068  9 0.007 1077  9 0.008 1088  9 0.010 1090  9 0.010 1106  90.014 1110  9 0.015 1116  9 0.016 1129  9 0.021 1131  9 0.022 1152  90.038 1153  9 0.039 1178  9 0.071 1198  9 0.143 1224  9 0.270 1226  90.282 1233  9 0.343 1261  9 0.932 1275  9 1.722 1277  9 1.834 1279  91.902 1286  9 2.417 1295  9 3.278 1302  9 4.948 1306  9 8.151 1320  9<0.005 1367  9 <0.005 1368  9 <0.005 1369  9 <0.005 1370  9 <0.005 1371 9 <0.005 1372  9 <0.005 1373  9 <0.005 1413  9 0.015 1492  9 >16.66861499  9 >16.6686 118  9b 0.664 119  9b 3.17 120  9b 0.0783 121  9b 1.91122  9b 5.97 123  9b 0.591 124  9b 0.118 0.321 125  9b 0.322 126  9b0.0510 0.0200 127  9b 0.499 128  9b 0.0045 129  9b 0.281 130  9b 0.823131  9b 0.0767 132  9b 0.880 568  9b 0.072 569  9b 0.021 571  9b 0.028573  9b 0.046 577  9b 0.052 578  9b 0.063 580  9b 0.069 583  9b 0.104584  9b 0.105 590  9b 0.186 599  9b 1.031 617  9b 0.102 566  9c 0.0141375  9c <0.005 1421  9c <0.005 582  9d 0.097 588  9d 0.142 594  9d0.449 1109  9d 0.015 1113  9d 0.016 1133  9d 0.024 1159  9d 0.045 1171 9d 0.063 1177  9d 0.063 1182  9d 0.079 633  9e 0.062 1115  9e 0.016 575 9f 0.051 576  9f 0.051 1080  9f 0.009 1374  9f <0.005 1376  9f <0.0051419  9f <0.005 1420  9f 0.005 1422  9f 0.014 1165  9g 0.051 1210  9g0.195 819  9h 2.790 601  9i 0.490 1.552 602  9i 0.302 1.717 607  9i0.894 2.905 608  9i 0.766 4.166 609  9i 0.735 4.332 980  9i 2.442 6.792989  9i 1.566 990  9i 3.870 991  9i 0.564 1252  9i 0.136 0.706 1255  9i<0.005 0.769 1290  9i 0.187 2.700 1387  9i 0.300 1388  9i 0.351 1389  9i0.379 1390  9i 0.461 1391  9i 0.505 1393  9i 0.726 1394  9i 0.756 1399 9i 2.373 1154  9j <0.005 0.040 1173  9j 0.065 1190  9j 0.099 1191  9j0.105 1193  9j 0.116 1220  9j 0.255 1237  9j 0.393 1238  9j <0.005 0.4371251  9j 0.684 1254  9j 0.023 0.765 1257  9j 0.827 1282  9j 0.019 2.072323 10 0.0110 324 10 <0.005 <0.005 325 10 0.0150 0.0695 686 10 0.039 74910 0.387 778 10 0.933 801 10 1.712 833 10 4.562 650 10a 0.006 666 10a0.013 670 10a 0.015 900 10a <0.005 659 10b 0.009 697 10b 0.062 901 10b<0.005 902 10b <0.005 326 11 <0.005 <0.005 327 11 0.0089 328 11 0.0540329 11 0.0358 1.22 330 11 0.0440 0.308 331 11 <0.005 0.0457 332 110.0117 333 11 <0.005 0.0162 334 11 0.0143 0.363 335 11 0.0060 0.0121 33611 <0.005 <0.005 337 11 <0.005 0.0130 504 11 <0.005 0.010 516 11 0.465543 11 <0.005 684 11 0.031 742 11 0.306 810 11 2.143 897 11 <0.005<0.005 898 11 <0.005 <0.005 908 11 0.031 929 11 <0.005 930 11 <0.005 33812 <0.005 <0.005 339 12 0.113 340 12 0.843 341 12 3.63 342 12 0.0440 34313 0.0059 344 13 0.0270 345 13 <0.005 <0.005 511 13 0.240 515 13 0.455591 13 0.212 346 14 2.83 347 14 0.0877 600 14 1.154 605 14 1.861 917 142.107 919 14 4.004 920 14 4.427 924 14 9.685 1059 14 0.006 1060 14 0.0061065 14 0.007 1066 14 0.007 1096 14 0.011 1101 14 0.012 1157 14 0.0411160 14 0.045 1183 14 0.085 1321 14 <0.005 1342 14 <0.005 1343 14 <0.0051351 14 <0.005 1352 14 <0.005 1353 14 <0.005 1354 14 <0.005 1075 14a0.008 1149 14a 0.035 1175 14a 0.066 1205 14a 0.168 1196 14b 0.123 120414b 0.166 1211 14b 0.200 1241 14b 0.460 1244 14b 0.463 1209 14c 0.1931213 14c 0.206 1294 14d 3.229 1303 14d 5.112 1443 14d >16.6686 147614d >16.6686 348 15 1.16 349 16 1.03 350 17 0.0991 351 17 1.97 352 171.67 353 17 3.97 354 17 1.56 546 17 1437 17 >16.6686 148617 >16.6686 >16.6686 538 17a 8.813 861 17a 9.221 903 17a 0.009 690 17b0.046 916 17b 1.683 355 18 2.05 356 19 1.62 357 20 0.0385 3.75 358 210.0670 359 21 0.0094 360 21 0.0060 361 21 0.0355 362 21 0.542 363 213.12 364 21 0.0085 0.210 365 21 0.0332 665 21 0.013 679 21 0.010 0.024685 21 0.029 0.033 729 21 0.236 736 21 <0.005 0.273 907 21 0.029 366 22<0.005 367 22 0.0080 368 22 0.0050 369 22 0.165 370 23 <0.005 371 23<0.005 879 23 0.006 <0.005 880 23 0.025 <0.005 680 23a 0.025 145823a >16.6686 372 24 <0.005 373 24 <0.005 374 24 <0.005 375 24 0.0414 66124 0.010 668 24 0.015 805 24 1.995 883 24 <0.005 376 25 1.08 377 25 3.35378 25 5.06 379 26 0.0367 380 26 0.0542 381 26 0.0099 <0.005 382 260.913 383 26 0.476 384 26 0.349 385 26 0.110 386 26 1.25 387 26 0.348388 26 0.429 389 26 9.27 390 26 2.43 391 26 0.227 392 26 0.558 393 260.141 394 26 0.434 395 26 0.437 396 26 0.790 397 27 0.0180 398 27 0.0254399 27 0.0312 400 27 <0.005 401 27 <0.005 402 27 0.0476 403 27 0.0958404 27 0.0418 405 27 0.0067 406 27 0.0831 407 27 <0.005 0.0506 408 270.239 409 27 1.39 481 27 0.244 482 27 0.236 483 27 0.338 484 27 0.696552 27 0.147 560 27 1.978 957 27 <0.005 <0.005 960 27 0.007 962 27<0.00500035 963 27 0.190 967 27 0.020 0.009 970 27 0.805 972 27 0.0130.023 983 27 0.006 987 27 0.071 554 27a 0.179 978 27a <0.00500035 0.007981 27a 0.186 958 27b 0.313 961 27b 1.122 968 27b 0.019 979 27b 0.648984 27b 2.497 410 28 0.0253 411 28 0.0478 412 28 0.0249 413 28 0.0406414 28 0.0144 415 28 0.0110 416 28 0.0129 417 28 0.197 418 28 0.315 55028 0.114 555 28 0.196 973 28 <0.005 975 28 1.174 0.162 974 28a 0.177 41929 0.0070 0.170 420 29 0.0112 421 29 0.0060 422 29 0.0568 423 29 0.0050424 29 <0.005 <0.005 425 29 0.160 426 29 0.278 662 29 0.021 0.011 93129a 427 30 0.0334 428 30 <0.005 429 30 <0.005 430 30 0.0180 0.0236 43130 <0.005 432 30 <0.005 <0.005 677 30a 0.021 790 30a 1.417 433 31 0.0249508 31 0.006 0.107 651 31 <0.005 0.007 738 31 0.065 0.289 876 31 <0.005<0.005 1507 31 >16.6686 564 31a 4.633 5.400 971 31a 1.536 976 31a 0.5660.574 977 31a 5.563 807 31b 2.075 914 31c 0.760 1493 31c >16.6686 149831c >16.6686 434 32 0.0647 435 32 0.0267 436 32 0.331 437 32 1.52 438 320.977 439 33 0.672 440 33 4.07 441 33 10.3 442 33 3.78 443 33 3.35 44433 3.22 445 33 2.28 446 33 2.36 447 33 0.667 448 33 1.90 449 33 8.12 45034 0.0088 451 34 0.652 452 34 0.288 453 35 <0.005 454 35 0.0060 455 35<0.005 548 35 0.027 959 35 0.005 <0.005 549 35a 0.104 551 35a 0.125 95635a 0.048 969 35a 0.077 955 35b 0.713 964 35b 1.701 456 36 1.98 457 370.876 458 37 3.72 459 37 0.950 460 37 0.548 497 38 2.36 498 38 0.679 49938 0.418 500 38 1.18 501 38 >16.7 495 39 >16.7 491 39 0.254 492 390.0788 493 39 0.169 494 39 0.0771 642 40 0.069 645 40 5.207 148841 >16.6686 1457 41 >16.6686 996 42 <0.005 997 42 <0.005 1006 42 0.3741016 42 0.085 547 42 <0.005 563 42 2.493 985 42 0.008 995 42 <0.005 99842 <0.005 999 42 0.008 1007 42 0.027 1008 42 <0.005 1009 42 0.065 101342 0.161 1014 42 0.257 1015 42 0.777 771 42 0.007 948 43 0.011 949 430.163 950 43 1.501 1025 43 0.019 507 44 0.013 0.052 518 44 1.605 520 442.027 522 44 2.680 525 44 6.995 527 44 3.512 8.566 532 44 1.419 533 441.804 537 44 7.588 652 44 0.007 663 44 <0.005 0.011 715 44 0.135 717 440.147 734 44 0.163 0.256 752 44 0.421 765 44 0.236 0.667 875 44 <0.005<0.005 877 44 0.012 <0.005 904 44 0.011 909 44 0.074 913 44 0.516 148444 >16.6686 802 44a 1.721 837 44a 5.036 869 44a 12.871 872 44a 13.954720 44b 0.173 757 44b 0.530 769 44b 0.725 784 44b 1.125 922 44b 6.494514 45 0.454 519 45 1.620 521 45 2.190 660 45 0.010 683 45 0.031 708 450.106 878 45 <0.005 1494 45a >16.6686 689 45b 0.045 803 45b 1.868 81145b 2.151 1010 46 <0.005 1011 46 <0.005 1018 46 0.101 1019 46 0.006 102146 0.015 1023 46 0.041 1024 46 0.069 1267 46 1.125 1304 46 6.035 1309 469.363 1012 46a 0.013 1020 46a 0.063 1022 46a 0.067 1311 46a 14.615 52947 0.147 530 47 0.165 542 47 <0.005 553 47 0.176 556 47 0.293 557 470.340 561 47 2.745 1005 47 0.237 709 48 0.118 671 49 0.016 1365 50<0.005 1417 51 <0.005 1418 51 0.016 1063 52 0.007 1092 52 0.011 1315 52<0.005 1316 53 <0.005 1317 53 <0.005 1319 53 <0.005 1142 53a 0.029 131853a <0.005 597 54 0.600 604 54 1.841 1086 54 0.009 1130 54 0.022 1137 540.026 1170 54 0.059 1195 54 0.120 884 55 <0.005 885 55 <0.005 1081 550.009 1099 55 0.012 881 55a <0.005 882 55a <0.005 994 55a 0.013 724 55b0.206 773 55b 0.845 1026 56 0.016 1027 56 0.014 1028 56 0.016 1033 56<0.005 1034 56 <0.005 992 57 7.761 1430 57 9.892 1431 57 0.589 911 580.272 988 58 0.036 612 59 0.016 613 59 0.019 614 59 0.025 615 59 0.026616 59 0.076 706 59 0.103 1074 59 0.014 0.008 1091 59 0.011 0.011 109359 <0.005 0.011 1104 59 <0.005 0.013 1108 59 0.019 0.014 1114 59 0.0161117 59 <0.005 0.016 1124 59 <0.005 0.019 1138 59 0.026 1144 59 0.0060.031 1168 59 <0.005 0.053 1172 59 0.010 0.063 1185 59 0.007 0.088 118859 0.027 0.094 1200 59 0.020 0.151 1208 59 <0.005 0.190 1221 59 0.0080.258 1228 59 0.249 0.295 1234 59 0.024 0.356 1239 59 0.338 0.449 124059 0.139 0.459 1250 59 0.174 0.638 1253 59 0.031 0.725 1259 59 0.0620.847 1265 59 0.072 1.050 1268 59 1.220 1273 59 0.234 1.609 1278 591.392 1.863 1280 59 0.239 1.978 1285 59 1.041 2.317 1288 59 1.123 2.5111322 59 <0.005 <0.005 1323 59 0.012 <0.005 1377 59 0.004 1405 59 <0.0051406 59 <0.005 1136 59a 0.025 1161 59a 0.046 1162 59a 0.047 1212 59a0.204 1260 59a 0.862 759 60 0.579 761 60 0.583 780 60 0.978 834 60 4.595841 60 5.257 851 60 7.870 1064 60 0.007 1167 60 0.053 1186 60 0.088 120760 0.179 1231 60 0.316 1270 60 1.429 1274 60 1.660 1281 60 2.023 635 60a0.838 777 60a 0.913 789 60a 1.366 798 60a 1.630 858 60a 8.772 866 60a10.325 1206 60a 0.171 1215 60a 0.216 1227 60a 0.287 1229 60a 0.306 126460a 0.986 1289 60a 2.603 1291 60a 2.785 1296 60a 3.299 1506 60a >16.6686932 60b 0.104 933 60b 0.191 934 60b 0.174 935 60b 0.100 936 60b 0.013937 60b 0.250 938 60b 0.698 939 60b 2.357 940 60b 2.237 941 60b 1.372942 60b 0.216 943 60b 10.387 944 60b 7.322 945 60b 1.476 509 61 0.136653 61 0.007 895 61 <0.005 585 62 0.107 593 62 0.311 701 62 0.077 108462 0.009 1100 62 0.012 1132 62 <0.005 0.023 1148 62 0.033 1155 62 0.0411347 62 <0.005 572 62a 0.031 634 62a 0.057 1340 62a <0.005 1341 62a<0.005 1344 62a <0.005 1345 62a <0.005 982 63 0.010 <0.005 986 64 0.005510 65 0.181 513 65 0.371 528 65 0.125 570 65 0.022 691 65 0.046 695 650.057 707 65 0.105 712 65 0.127 714 65 0.135 737 65 0.285 1058 65 0.0061095 65 0.011 1098 65 0.012 1346 65 <0.005 951 66 0.540 506 67 0.048 67367 0.017 896 67 <0.005 512 67a 0.260 664 67a 0.011 699 67a 0.069 505 67b<0.005 0.039 657 67b 0.009 674 67b <0.005 0.019 692 67b 0.047 899 67b<0.005 <0.005 649 68 0.006 700 68 0.072 704 68a 0.096 705 68a 0.099 57469 0.049 589 69 0.146 631 70 0.040 632 70 0.281 1069 70 0.007 1348 70<0.005 1349 70 <0.005 1111 70a 0.016 1350 70a <0.005 1076 70b 0.008 135570b <0.005 1414 70c 0.011 1415 70c 0.115 1416 70c 0.039 711 71 0.127 81371 2.422 1031 71 0.111 1032 71 3.020 1035 71 4.622 1046 71 0.288 1047 714.628 1048 71 0.695 1029 72 <0.005 1030 72 0.013 1036 72 <0.005 1037 720.005 1038 72 <0.005 1039 72 0.005 1040 72 0.025 1043 72 0.016 1049 720.010 1050 72 0.024 1051 72 0.128 1052 72 0.028 1411 72 0.012 1044 72a0.718 1045 72a 0.021 1508 0.046

Example 2 2-AG Accumulation assay

To measure the accumulation of 2-AG due to inhibition of MGL, one g ratbrain was homogenized using a Polytron homogenizer (Brinkmann, PT300) in10 mL of 20 mM HEPES buffer (pH=7.4), containing 125 mM NaCl, 1 mM EDTA,5 mM KCl and 20 mM glucose. Compounds of Formula (I) (10 μM) werepre-incubated with rat brain homogenate (50 mg). After a 15-minincubation time at 37° C., CaCl₂ (final concentration=10 mM) was addedand then incubated for 15 min at 37° C. in a total volume of 5 mL. Thereactions were stopped with 6 mL organic solvent extraction solution of2:1 chloroform/methanol. Accumulated 2-AG in the organic phase wasmeasured by a HPLC/MS method, according to the following equation:percent vehicle=(2-AG accumulation in the presence of compound/2-AGaccumulation in vehicle)×100.

BIOLOGICAL DATA TABLE 2 Rat Brain 2AG % VehCntrl Chemistry (%) (%) CpdExample @0.01 μM @0.1 μM (%) @1 μM (%) @10 μM 2  1 911 5  1 122 123 156279 6  1 75 238 554 623 7  1 216 238 568 9  1 99 184 529 1026 12  1 44813  1 730 567  1 455 579  1 265 581  1 140 587  1 148 595  1 128 1061  1618 1071  1 552 1139  1 654 1147  1 892 1163  1 244 1174  1 1021 1201  1475 1356  1 1420 1357  1 2570 1358  1 1183 1359  1 1016 1360  1 576 1361 1 994 1362  1 635 1363  1 628 1364  1 944 1366  1 586 1382  1 293 1408 1 1475 487  1a 463 2081 2182 1062  1b 451 1072  1b 839 1073  1b 7491089  1b 545 1097  1b 422 1105  1b 734 1107  1b 838 1120  1b 867 1126 1b 850 1134  1b 774 1135  1b 884 1176  1b 378 1181  1b 288 1312  1b 9631337  1b 979 1338  1b 877 1339  1b 574 1184  1c 401 1141  1d 148 442 9961151  1d 482 1158  1d 1623 1125  1e 1228 1187  1e 319 1313  1f 851 39  2173 168 277 40  2 490 41  2 544 43  2 215 44  2 238 61  3 604 676  3 437703  3 346 716  3 326 722  3 240 741  3 182 753  3 173 1067  3 408 1166 3 176 1235  3 100 1236  3 167 1283  3 62 72  4 334 75  4 193 77  4 23183  4 105 133  5 623 134  5 582 135  5 592 136  5 612 137  5 441 138  5661 147  5 676 148  5 744 150  5 1104 158  5 126 213 161  5 335 1280 162 5 1099 163  5 923 164  5 969 166  5 509 167  5 481 168  5 813 170  5205 172  5 217 476  5 272 115  5 579 485  5 208 396 818 489  5 119 235790 950 490  5 208 343 756 886 636  5 296 637  5 272 641  5 397 648  5126 655  5 359 658  5 351 667  5 856 669  5 583 672  5 268 675  5 330678  5 234 682  5 390 687  5 698 688  5 373 693  5 299 696  5 444 702  5848 886  5 823 887  5 270 888  5 940 889  5 683 890  5 823 891  5 422892  5 948 893  5 626 894  5 534 905  5 119 965  5 591 1017  5 307 1082 5 742 1083  5 299 1103  5 698 1122  5 143 1150  5 139 459 715 1156  5681 1164  5 250 1179  5 996 1326  5 944 1327  5 966 1328  5 1086 1329  5834 1330  5 589 1331  5 803 1332  5 1168 1333  5 824 1378  5 493 1379  5282 1381  5 604 1384  5 313 1407  5 1287 174  6 1258 175  6 330 706 1180176  6 1124 177  6 768 178  6 1192 179  6 910 180  6 703 181  6 1236 182 6 1500 183  6 1090 184  6 956 186  6 123 199 260 521 188  6 506 195  6365 196  6 516 205  6 1172 207  6 402 208  6 480 324 209  6 1681 210  6122 211  6 725 212  6 831 213  6 104 214  6 769 215  6 1091 216  6 625218  6 764 219  6 851 220  6 993 221  6 945 223  6 1261 224  6 906 225 6 656 226  6 652 227  6 938 228  6 710 229  6 276 552 1304 230  6 567232  6 152 427 237  6 1044 1182 239  6 153 290 1097 1353 240  6 184 538639 243  6 120 245  6 224 518 829 248  6 312 250  6 180 472 1011 1327251  6 144 586 791 253  6 107 319 624 254  6 544 255  6 115 256  6 157257  6 285 259  6 156 260  6 140 261  6 148 525 856 262  6 386 263  6199 264  6 172 265  6 126 162 643 266  6 395 267  6 130 268  6 110 488 6 219 247.5 681 1070  6 551 1102  6 878 273  7 623 274  7 876 281  7201 282  7 1775 283  7 605 291  7 1019 310  8 141 311  8 125 312  8 1981140  8 200 1325  8 575 186-A  8 149 1465  8 110 313  9 814 314  9 175237 512 553 316  9 243 265 760 694 317  9 417 318  9 537 319  9 396 321 9 230 654  9 389 681  9 406 713  9 718  9 723  9 745  9 767  9 775  9806  9 812  9 817  9 820  9 822  9 829  9 832  9 856  9 918  9 1054  91008 1055  9 701 1056  9 498 1068  9 849 1077  9 667 1088  9 760 1090  91106  9 784 1110  9 807 1116  9 828 1129  9 437 1131  9 563 1152  9 3941153  9 404 1178  9 292 1198  9 1224  9 1226  9 1233  9 1261  9 1275  91277  9 1279  9 1286  9 1295  9 1302  9 1306  9 1320  9 823 1367  9 7981368  9 859 1369  9 874 1370  9 773 1371  9 827 120  9b 483 126  9b 128138 328 715 128  9b 688 129  9b 499 131  9b 1406 569  9b 198 571  9b 307573  9b 277 577  9b 207 580  9b 179 582  9d 169 1109  9d 680 1113  9d819 1133  9d 296 1159  9d 654 1171  9d 839 1177  9d 895 1182  9d 5471255  9i 147 1154  9j 558 1173  9j 133 1190  9j 126 1254  9j 187 1282 9j 128 323 10 494 324 10 941 1215 1265 325 10 478 686 10 552 650 10a960 666 10a 359 670 10a 650 900 10a 543 659 10b 576 697 10b 431 901 10b816 902 10b 585 326 11 1336 327 11 904 2005 328 11 378 329 11 520 330 11197 331 11 310 332 11 182 333 11 291 334 11 259 335 11 170 438 839 1059336 11 223 337 11 103 166 272 671 504 11 178.5 543 11 158 684 11 645 89711 1234 898 11 520 908 11 217 929 11 301 930 11 807 338 12 2111 791 34212 288 343 13 1371 344 13 238 345 13 744 347 14 125 1059 14 507 1060 14671 1065 14 531 1066 14 609 1096 14 449 1101 14 501 1157 14 252 1160 14260 1183 14 549 1342 14 346 1343 14 838 1351 14 718 1352 14 548 1353 14545 1354 14 750 1075 14a 833 350 17 498 903 17a 908 690 17b 367 357 20152 358 21 556 359 21 176 360 21 819 361 21 186 364 21 581 365 21 971665 21 507 679 21 751 685 21 756 736 21 499 907 21 867 366 22 432 367 22701 368 22 434 906 22 896 927 22 850 928 22 1207 370 23 888 371 23 1138879 23 1027 880 23 945 680 23a 356 661 24 764 668 24 679 883 24 767 37926 760 380 26 773 381 26 520 397 27 243 398 27 392 400 27 1076 401 27762 402 27 97 403 27 188 405 27 1591 406 27 99 407 27 127 441 743 957 271442 960 27 896 962 27 1213 967 27 1373 972 27 683 983 27 194 987 27 320978 27a 570 968 27b 360 410 28 720 411 28 741 412 28 1271 413 28 1693414 28 1608 415 28 1629 416 28 228 973 28 806 419 29 109 422 29 120 42329 529 424 29 436 662 29 274.5 427 30 163 428 30 734 429 30 318 430 30114 431 30 703 432 30 321 677 30a 141 433 31 159 508 31 119 651 31 258876 31 363 434 32 737 435 32 198 453 35 917 454 35 1066 455 35 1013 54835 280 959 35 861 956 35a 514 969 35a 515 494 39 1121 642 40 170 996 42458 997 42 761 1016 42 536 547 42 652 985 42 1116 995 42 1080 998 42 639999 42 458 1007 42 180 1008 42 1125 1009 42 706 771 42.9 465 1025 43 851507 44 190 518 44 86 663 44 588 875 44 232 499 1285 877 44 475 904 44392 909 44 144 660 45 410 683 45 335 878 45 288 689 45b 136 1010 46 19531011 46 994 1019 46 287 1021 46 232 1023 46 262 1024 46 281 1012 46a 1731020 46a 135 1022 46a 189 542 47 366 671 49 1035 1365 50 909 1063 52 8461092 52 838 1315 52 486 1316 53 602 1317 53 722 1319 53 1276 1142 53a1314 1318 53a 1282 1086 54 488 1130 54 553 1137 54 582 1170 54 258 88455 425 885 55 722 1081 55 622 1099 55 508 881 55a 847 882 55a 697 99455a 1014 1026 56 1014 1027 56 785 1028 56 647 612 59 106 613 59 165 61459 87 615 59 123 616 59 92 1074 59 303 1091 59 450 1093 59 472 1104 59334 1108 59 117 204 456 1114 59 293 1117 59 437 1124 59 506 1138 59 2711144 59 212 1168 59 780 1172 59 931 1185 59 241 1188 59 187 1200 59 2311208 59 212 1221 59 198 197.5 522 1234 59 226 1253 59 110 190 407 125959 159 1265 59 192 1322 59 457 1323 59 297 1405 59 197 1406 59 169 113659a 325 1161 59a 459 1162 59a 237 1064 60 570 1167 60 345 1186 60 393509 61 242 653 61 861 895 61 1207 701 62 475 1084 62 1165 1100 62 11331132 62 1259 1148 62 344 1155 62 617 1347 62 741 572 62a 397 634 62a 3011340 62a 761 1341 62a 1149 1344 62a 543 1345 62a 459 982 63 762 986 64626 570 65 210 691 65 840 695 65 497 1058 65 590 1095 65 484 1098 65 2961346 65 406 506 67 132 673 67 280 896 67 648 664 67a 498 699 67a 253 50567b 236.5 657 67b 581 674 67b 891 692 67b 284 899 67b 1092 649 68 1017700 68 547 705 68a 487 574 69 207 1069 70 696 1348 70 1428 1349 70 8461111 70a 508 1350 70a 873

Example 3 MGL ThermoFluor® Assay-Mutant

The ThermoFluor (TF) assay is a 384-well plate-based binding assay thatmeasures thermal stability of proteins^(1,2). The experiments werecarried out using instruments available from Johnson & JohnsonPharmaceutical Research & Development, LLC. TF dye used in allexperiments was 1,8-ANS (Invitrogen: A-47). Final TF assay conditionsused for MGL studies were 0.07 mg/ml of mutant MGL, 100 μM ANS, 200 mMNaCl, 0.001% Tween-20 in 50 mM PIPES (pH=7.0).

Screening compound plates contained 100% DMSO compound solutions at asingle concentration. For follow-up concentration-response studies,compounds were arranged in a pre-dispensed plate (Greiner Bio-one:781280), wherein compounds were serially diluted in 100% DMSO across 11columns within a series. Columns 12 and 24 were used as DMSO referenceand contained no compound. For both single and multiple compoundconcentration-response experiments, the compound aliquots (46 mL) wererobotically predispensed directly into 384-well black assay plates(Abgene: TF-0384/k) using the Hummingbird liquid handler. Followingcompound dispension, protein and dye solutions were added to achieve thefinal assay volume of 3 μL. The assay solutions were overlayed with 1 μLof silicone oil (Fluka, type DC 200: 85411) to prevent evaporation.

Bar-coded assay plates were robotically loaded onto a thermostaticallycontrolled PCR-type thermal block and then heated from 40 to 90° C.degrees at a ramp-rate of 1° C./min for all experiments. Fluorescencewas measured by continuous illumination with UV light (Hamamatsu LC6),supplied via fiber optics and filtered through a band-pass filter(380-400 nm; >60D cutoff). Fluorescence emission of the entire 384-wellplate was detected by measuring light intensity using a CCD camera(Sensys, Roper Scientific) filtered to detect 500±25 nm, resulting insimultaneous and independent readings of all 384 wells. A single imagewith 20-sec exposure time was collected at each temperature, and the sumof the pixel intensity in a given area of the assay plate was recordedvs temperature and fit to standard equations to yield the T_(m) ¹.

-   1. Pantoliano, M. W., Petrella, E. C., Kwasnoski, J. D., Lobanov, V.    S., Myslik, J., Graf, E., Carver, T., Asel, E., Springer, B. A.,    Lane, P., and Salemme, F. R. (2001) J Biomol Screen 6, 429-40.-   2. Matulis, D., Kranz, J. K., Salemme, F. R., and Todd, M. J. (2005)    Biochemistry 44, 5258-66.

The K_(d) values for compounds of Formula (I) were determined from a fitof the equation to the concentration-response plot of the fractionalactivity as a function of T_(n). For some experiments, quantitative NMRspectroscopy (qNMR) was used to measure concentration of the initial100% DMSO compound solutions and, using the same fitting method, qK_(d)values were determined

BIOLOGICAL DATA TABLE 3 MGL mutant MGL mutant ThermoFluor qKd (μM) CpdExample ThermoFluor Kd (μM) (using qNMR conc.) 1  1 0.00590 2  1 0.000493  1 2.50 4  1 0.143 5  1 0.0548 6  1 0.00360 7  1 0.0466 8  1 0.111 9 1 0.00248 10  1 0.556 11  1 0.454 12  1 0.0143 13  1 0.00300 14  10.250 15  1 0.286 22  1 >76.7 23  1 5.00 24  1 5.00 25  1 10.0 26  13.33 567  1 0.051 579  1 0.067 581  1 0.100 587  1 0.473 595  1 0.404598  1 0.249 1071  1 0.025 1139  1 0.017 1147  1 0.003 1163  1 0.0731174  1 0.015 1201  1 0.179 1248  1 0.043 1356  1 0.002 1357  1 0.0021358  1 0.007 1359  1 0.008 1360  1 0.008 1361  1 0.003 1362  1 0.0011363  1 0.014 1364  1 0.001 1366  1 0.012 1382  1 0.197 1408  1 0.012487  1a 0.00240 586  1b 0.086 596  1b 0.628 603  1b 0.448 630  1b 0.1951062  1b 0.100 1072  1b 0.007 1073  1b 0.087 1089  1b 0.009 0.006 1097 1b 0.032 1105  1b 0.023 1107  1b 0.003 1120  1b 0.020 1121  1b 0.0421126  1b 0.008 1127  1b 0.098 1128  1b 0.018 1134  1b 0.009 1135  1b0.015 1176  1b 0.161 1181  1b 0.278 1189  1b 0.153 1192  1b 0.035 1197 1b 0.065 1216  1b 0.022 1219  1b 0.025 1230  1b 0.009 1247  1b 0.6501263  1b 0.215 1312  1b 0.008 1314  1b 0.001 1337  1b 0.040 1338  1b0.015 1339  1b 0.013 1410  1b 0.014 656  1c 0.101 1079  1c 0.272 1184 1c 0.244 1199  1c 0.264 1141  1d 0.088 1151  1d 0.048 1158  1d 0.008592  1e 0.500 1125  1e 0.037 1187  1e 0.197 629  1f 0.145 1180  1f 0.0191313  1f 0.003 0.001 1409  1g 27  2 4.55 28  2 0.370 29  2 0.100 30  20.118 31  2 1.43 32  2 0.192 33  2 0.00910 34  2 0.588 35  2 0.0833 36 2 0.0370 37  2 0.100 38  2 0.182 39  2 0.0250 40  2 0.0242 41  20.00400 42  2 0.0833 47  2 0.0909 48  2 1.00 49  2 6.67 50  2 10.0 51  20.250 52  2 3.33 53  2 0.100 55  2 25.0 470  2 2.94 471  2 2.50 472  26.67 531  2 2.733 539  2 >31.2464 541  2 1.662 559  2 100.000 562 2 >31.2464 565  2 >31.2464 622  2 3.601 627  2 10.000 628  2 100.000954  2 3.438 1266  2 0.032 1284  2 0.041 1404  2 >31.2464 1482 2 >31.2464 1483  2 >31.2464 1485  2 10.000 1464  2 >31.2464 61  30.0290 676  3 0.029 703  3 0.050 716  3 0.040 722  3 0.082 741  3 0.200753  3 0.515 921  3 4.260 1067  3 0.007 1166  3 0.010 1235  3 0.124 1236 3 0.031 1242  3 0.197 1243  3 0.033 1246  3 0.042 1276  3 0.807 1283  30.523 1292  3 0.631 1383  3 0.108 1400  3 4.071 1401  3 1.250 1402  32.000 76  4 0.333 77  4 0.00909 78  4 0.0800 79  4 0.0266 80  4 49.5 81 4 0.0667 82  4 0.571 83  4 0.111 474  4 5.00 103  4 6.25 104  4 5.00105  4 5.00 106  4 0.154 107  4 0.556 108  4 1.25 109  4 0.0333 110  45.00 111  4 10.0 496  4 0.287 558  4 0.333 618  4 0.080 619  4 0.172 620 4 0.154 621  4 0.263 623  4 1.000 624  4 0.880 625  4 >31.2464 626  45.018 150  5 0.00330 151  5 0.0250 158  5 0.476 161  5 0.0112 162  50.00067 163  5 0.00345 164  5 0.00111 166  5 0.00500 167  5 0.0558 168 5 0.0100 169  5 30.3 170  5 0.0606 171  5 0.708 172  5 0.100 475  50.0250 476  5 0.0667 477  5 2.00 478  5 2.00 479  5 6.67 298  5 2.91 113 5 1.11 114  5 0.00333 115  5 0.0370 116  5 2.00 489  5 0.0104 490  50.00840 485  5 0.0257 502  5 >76.6655 503  5 0.254 517  5 0.050 523  50.686 524  5 1.667 526  5 4.984 610  5 1.295 611  5 5.152 636  5 0.119637  5 0.053 638  5 0.172 0.264 639  5 0.132 640  5 24.998 641  5 0.1180.136 643  5 1.000 644  5 >76.6655 646  5 1.608 648  5 0.146 655  50.029 658  5 0.402 667  5 0.013 669  5 0.005 672  5 0.016 675  5 0.025678  5 0.031 682  5 0.014 687  5 0.004 688  5 0.046 693  5 0.060 694  50.048 696  5 0.063 698  5 0.085 702  5 0.207 710  5 0.197 719  5 0.119721  5 1.138 726  5 0.127 727  5 0.251 728  5 730  5 0.146 731  5 0.016732  5 0.002 733  5 0.453 735  5 0.160 739  5 0.265 740  5 0.035 743  50.133 744  5 746  5 0.263 747  5 0.111 748  5 0.040 750  5 0.025 751  51.320 755  5 0.328 756  5 0.383 758  5 0.500 760  5 0.199 762  5 1.000763  5 0.083 766  5 0.378 770  5 1.132 772  5 0.185 774  5 0.254 776  50.257 779  5 0.100 782  5 0.463 783  5 0.732 785  5 0.500 786  5 0.665787  5 0.247 788  5 1.980 791  5 0.402 792  5 0.973 793  5 0.198 794  52.113 795  5 1.105 796  5 0.099 797  5 0.489 799  5 0.661 800  5 1.100804  5 0.105 808  5 62.503 809  5 0.769 814  5 >31.0027 815  5 0.250 816 5 2.842 818  5 1.000 823  5 1.251 824  5 0.074 825  5 4.855 826  50.663 827  5 0.500 828  5 2.633 830  5 1.963 831  5 0.270 835  5 2.454836  5 2.252 838  5 0.978 839  5 2.500 840  5 2.000 842  5 0.986 843  52.134 844  5 62.503 845  5 1.619 848  5 0.833 849  5 2.697 850  5 1.000852  5 1.977 853  5 1.000 854  5 100.000 857  5 3.334 859  5 1.429 860 5 1.759 862  5 >21.8726 863  5 4.367 864  5 2.410 865  5 2.500 868 5 >23.126 873  5 9.198 874  5 8.461 887  5 0.009 888  5 0.000 889  50.002 890  5 0.001 891  5 0.008 892  5 0.007 893  5 0.005 894  5 0.006905  5 0.044 910  5 1.331 912  5 1.319 915  5 5.000 923  5 9.931 925 5 >62.5029 926  5 9.443 946  5 1.693 947  5 0.653 952  5 0.019 953 5 >26.872 965  5 0.035 966  5 0.334 993  5 0.333 1017  5 0.049 1041  50.397 1042  5 5.000 1053  5 0.247 1082  5 0.003 1083  5 0.065 1119  50.020 1122  5 0.027 1123  5 1.351 1146  5 0.080 1150  5 0.013 1156  50.090 1179  5 0.005 1194  5 0.100 1202  5 0.065 1203  5 0.015 1223  50.111 1225  5 0.042 1245  5 0.317 1249  5 0.241 1271  5 1.000 1272  50.399 1287  5 0.495 1293  5 1.667 1298  5 0.474 1299  5 1.100 1300  53.334 1305  5 0.833 1307  5 4.207 1326  5 0.004 1327  5 0.005 1328  50.002 1329  5 0.006 1330  5 0.002 0.005 1331  5 0.010 1332  5 0.008 1333 5 0.040 1334  5 0.080 1378  5 0.025 1379  5 0.042 1381  5 0.083 1384  50.061 1385  5 0.206 1386  5 0.133 1392  5 0.659 1395  5 1.805 1396  50.317 1397  5 0.500 1403  5 1.688 1407  5 0.005 1412  5 0.241 1444 5 >31.0027 1445  5 >31.2464 1491  5 12.500 1434  5 53.753 1477 5 >31.2464 1432  5 >28.4381 1489  5 100.000 1490  5 >31.2464 1481 5 >31.2464 1436  5 100.000 1473  5 6.667 1475  5 >31.2464 1446  562.503 1447  5 3.334 1448  5 7.091 1449  5 3.194 1450  5 12.639 1451 5 >16.248 1452  5 5.424 1453  5 10.000 223  6 0.00670 225  6 0.0200 226 6 0.0200 229  6 0.0125 231  6 0.143 233  6 1.32 234  6 0.0476 235  60.588 236  6 0.200 237  6 0.00100 238  6 0.0333 239  6 0.00500 240  60.0232 241  6 0.00050 242  6 0.00400 243  6 0.0167 244  6 0.00200 245  60.00950 246  6 0.0167 247  6 0.00040 248  6 0.00670 249  6 0.0100 250  60.00170 251  6 0.0143 252  6 0.0500 253  6 0.0215 254  6 0.00590 255  60.0270 256  6 0.0333 257  6 0.00330 258  6 0.00330 259  6 0.00770 260  60.0200 261  6 0.00910 262  6 0.00250 263  6 0.00500 264  6 0.0100 265  60.0198 266  6 0.0160 267  6 0.0125 268  6 0.0250 488  6 0.321 1070  60.006 1102  6 0.006 295  7 0.833 296  7 0.476 297  7 0.333 308  8 10.0309  8 0.253 310  8 0.250 311  8 0.0800 312  8 0.0250 480  8 >76.7 1057 8 0.016 1078  8 0.005 1085  8 0.008 1087  8 0.023 1094  8 0.012 1112  80.046 1118  8 0.053 1140  8 0.112 1143  8 0.070 1145  8 0.061 1169  80.053 1217  8 0.104 1222  8 0.068 1232  8 0.345 1256  8 0.393 1258  80.020 1262  8 0.278 1269  8 1.165 1308  8 2.056 1310  8 8.348 1324  80.016 1325  8 0.006 1335  8 0.011 1336  8 0.002 1398  8 0.182 1423  80.176 1424  8 0.124 1425  8 0.019 1426  8 0.029 1427  8 0.010 1428  80.018 1429  8 0.097 186-A  8 0.016 567-A  8 0.124 1478  8 >31.2464 1465 8 >31.2464 314  9 0.0392 316  9 0.0165 317  9 0.0100 318  9 0.0165 606 9 0.067 647  9 >31.2464 654  9 0.040 681  9 0.067 713  9 0.100 718  90.072 723  9 0.292 745  9 0.283 767  9 775  9 0.333 806  9 0.989 812  90.644 817  9 820  9 0.996 822  9 829  9 0.500 832  9 0.059 856  9 0.855918  9 2.500 1054  9 0.001 0.001 1055  9 0.020 1056  9 0.012 1068  90.002 1077  9 0.020 1088  9 0.001 1090  9 0.010 1106  9 0.006 0.005 1110 9 0.010 1116  9 0.001 1129  9 0.074 1131  9 0.016 1152  9 0.007 1153  90.004 1178  9 0.238 1198  9 0.030 1224  9 0.189 1226  9 0.193 1233  90.190 1261  9 0.831 1277  9 2.722 1279  9 1.864 1286  9 0.032 1295  91.509 1302  9 2.500 1306  9 12.193 1320  9 0.015 1367  9 0.002 1368  90.001 1369  9 0.002 1370  9 0.013 1371  9 0.003 1372  9 0.002 1373  90.004 1413  9 0.003 1492  9 18.763 1499  9 60.618 126  9b 0.0921 128  9b0.00400 129  9b 0.0100 130  9b 0.250 131  9b 0.0941 132  9b 0.250 568 9b 0.099 569  9b 0.059 571  9b 0.046 0.080 573  9b 0.100 577  9b 0.026578  9b 0.195 580  9b 0.118 583  9b 0.051 590  9b 0.182 599  9b 0.481566  9c 0.031 1375  9c 0.003 1421  9c 0.044 582  9d 0.119 588  9d 0.512594  9d 0.743 1109  9d 0.022 1113  9d 0.010 1133  9d 0.036 1159  9d0.003 1171  9d 0.024 1177  9d 0.088 1182  9d 0.210 633  9e 0.157 1115 9e 0.005 575  9f 0.083 576  9f 0.088 1080  9f 0.006 1374  9f 0.007 1376 9f 0.013 1419  9f 0.004 1420  9f 0.080 1422  9f 0.195 1165  9g 0.0901210  9g 0.097 601  9i 0.527 602  9i 0.500 607  9i 1.000 608  9i 1.674609  9i 1.000 980  9i 5.000 989  9i 1.250 990  9i 1.000 991  9i 0.2001252  9i 0.386 1255  9i 0.048 1290  9i 0.643 1389  9i 0.422 1154  9j0.006 1173  9j 0.007 1190  9j 0.008 1191  9j 0.011 1193  9j 0.017 1220 9j 0.015 1237  9j 0.064 1238  9j 0.125 1251  9j 0.146 1254  9j 0.1001257  9j 0.009 1282  9j 0.200 1380  9j 0.246 323 10 0.00130 324 100.00040 325 10 0.0927 686 10 0.002 749 10 0.036 778 10 1.195 801 1052.505 833 10 3.334 666 10a 0.002 0.003 670 10a 0.001 0.001 900 10a0.001 0.001 659 10b 0.006 697 10b 0.024 901 10b 0.001 902 10b 0.004 32611 0.00040 327 11 0.0137 328 11 0.0816 329 11 0.0626 330 11 0.438 331 110.00690 332 11 0.109 333 11 0.00390 334 11 0.132 335 11 0.00193 336 110.00950 337 11 0.0498 504 11 0.024 516 11 0.040 543 11 0.038 684 110.004 742 11 0.020 810 11 0.290 897 11 0.002 898 11 0.009 908 11 0.093929 11 0.020 930 11 0.005 338 12 0.00110 343 13 0.00040 344 13 0.0100345 13 0.00310 511 13 0.002 515 13 0.011 591 13 0.007 347 14 0.125 60014 1.968 605 14 1.892 917 14 4.995 919 14 100.000 920 14 100.000 924 14100.000 1059 14 0.066 1060 14 0.032 1065 14 0.036 1066 14 0.031 1096 140.080 1101 14 0.044 1157 14 0.179 1160 14 0.139 1183 14 0.067 1321 140.067 1342 14 0.136 1343 14 0.077 1351 14 0.043 1352 14 0.008 1353 140.018 1354 14 0.009 1075 14a 0.010 1149 14a 0.004 1175 14a 0.010 120514a 0.008 1196 14b 0.370 1204 14b 0.249 1211 14b 0.106 1241 14b 0.6381244 14b 0.589 1209 14c 0.942 1213 14c 0.765 1294 14d 4.412 1303 14d7.115 1443 14d >31.2464 1476 14d 7.208 546 17 12.365 1437 17 33.335 148617 >31.2464 538 17a 2.594 861 17a 2.625 903 17a 0.078 690 17b 0.104 35720 0.238 358 21 0.0650 359 21 0.0829 360 21 0.0680 361 21 0.144 362 212.40 363 21 6.76 665 21 0.058 685 21 0.067 729 21 0.185 736 21 0.067 36622 0.0353 367 22 0.0853 368 22 0.0551 370 23 0.00100 680 23a 0.053 145823a 100.000 372 24 0.0494 373 24 0.00550 374 24 0.00220 375 24 0.229 66124 0.047 668 24 0.025 805 24 6.405 883 24 0.059 376 25 7.14 377 25 >76.7378 25 >76.7 379 26 0.0400 393 26 0.0909 394 26 0.846 395 26 0.159 39626 4.27 397 27 0.0333 398 27 0.0869 399 27 0.0408 401 27 0.00167 402 270.141 403 27 0.338 404 27 0.00170 405 27 0.00200 406 27 0.932 407 270.0988 408 27 1.94 409 27 2.03 483 27 0.0200 552 27 0.400 560 27 0.652957 27 0.008 960 27 0.036 962 27 0.005 963 27 0.102 967 27 0.044 970 270.535 972 27 0.080 983 27 0.019 987 27 0.327 554 27a 1.985 978 27a 0.066981 27a 0.937 958 27b 0.216 961 27b 0.576 968 27b 1.462 979 27b 1.143984 27b 1.429 410 28 0.0333 411 28 0.0333 412 28 0.0100 413 28 0.00200414 28 0.0250 415 28 0.00800 416 28 0.160 417 28 0.0667 418 28 0.500 55528 2.000 975 28 2.000 974 28a 1.776 419 29 0.123 420 29 0.00500 421 290.00400 422 29 0.0532 423 29 0.00690 424 29 0.00941 425 29 0.200 426 290.250 662 29 0.100 427 30 0.0335 428 30 0.00330 429 30 0.0331 430 300.0667 432 30 0.0250 677 30a 0.432 790 30a 2.494 508 31 0.162 651 310.025 738 31 0.291 564 31a 10.000 976 31a 1.837 977 31a 19.999 807 31b3.652 450 34 0.0500 452 34 0.200 453 35 0.0120 454 35 0.0147 455 350.00850 548 35 0.062 959 35 0.044 549 35a 0.060 551 35a 0.180 956 35a0.081 969 35a 0.069 955 35b 1.111 964 35b 3.198 456 36 >76.7 457 37 4.82458 37 6.67 459 37 3.33 460 37 9.10 491 39 0.100 492 39 0.167 493 390.0250 494 39 0.100 642 40 0.499 645 40 5.443 1488 41 >31.2464 145741 >31.2464 997 42 0.041 1006 42 0.667 1016 42 0.460 547 42 0.072 563 422.106 985 42 0.005 995 42 0.002 1007 42 0.259 1008 42 0.089 1009 420.589 1013 42 0.760 1014 42 0.903 1015 42 1.183 771 42 0.050 948 430.030 949 43 0.178 950 43 0.883 1025 43 0.066 507 44 0.317 520 44 2.000522 44 4.708 525 44 2.500 527 44 10.000 532 44 2.331 533 44 10.000 53744 3.334 663 44 0.020 715 44 0.167 717 44 0.067 734 44 1.255 752 440.095 765 44 3.094 875 44 0.010 877 44 0.100 904 44 0.633 909 44 0.325913 44 1.000 1484 44 19.999 802 44a 1.667 837 44a 19.999 869 44a 6.202872 44a 10.000 720 44b 0.347 757 44b 0.781 769 44b 2.000 784 44b 2.149922 44b 3.890 514 45 0.727 519 45 0.962 660 45 0.065 683 45 0.039 878 450.088 1494 45a 7.377 803 45b 2.126 811 45b 3.334 1010 46 0.017 0.0401011 46 0.124 1018 46 0.207 1019 46 0.166 0.132 1021 46 0.239 1023 460.143 1024 46 0.135 1267 46 0.741 1304 46 7.903 1309 46 6.540 1012 46a3.337 1020 46a 3.004 1022 46a 0.228 1.061 1311 46a 67.499 529 47 0.317530 47 0.089 542 47 0.014 553 47 0.372 556 47 0.097 557 47 0.114 561 470.542 1005 47 0.083 709 48 0.015 671 49 0.018 1365 50 0.002 1417 510.025 1418 51 0.054 1063 52 0.003 1092 52 0.005 1315 52 0.002 1316 530.002 1317 53 0.002 1319 53 0.001 1142 53a 0.001 1318 53a 0.000 597 540.153 1137 54 0.010 1170 54 0.014 1195 54 0.023 884 55 0.017 885 550.001 1081 55 0.019 1099 55 0.020 881 55a 0.006 882 55a 0.012 994 55a0.002 724 55b 0.050 773 55b 0.040 1026 56 0.001 1027 56 0.012 1028 560.011 1033 56 0.000 1034 56 0.000 992 57 0.561 1430 57 50.003 1431 570.035 911 58 0.333 988 58 0.040 612 59 0.078 613 59 0.051 614 59 0.066615 59 0.097 616 59 >76.6655 706 59 0.001 1074 59 0.011 1091 59 1.6441093 59 0.240 1104 59 0.199 1108 59 0.063 1114 59 0.049 1117 59 0.2141124 59 0.250 1138 59 0.018 1144 59 0.181 1168 59 0.067 1172 59 0.1781185 59 1.318 1188 59 0.855 1200 59 0.500 1208 59 1.000 1221 59 0.0811228 59 1.422 1234 59 0.394 1239 59 3.040 1240 59 2.488 1250 59 2.0001253 59 0.088 1259 59 0.667 1265 59 0.660 1268 59 0.039 1273 59 1.8271278 59 5.192 1280 59 6.422 1285 59 2.450 1288 59 2.159 1322 59 0.0021323 59 0.004 1377 59 0.006 1405 59 0.002 1406 59 0.029 1161 59a 0.0251162 59a 0.014 1260 59a 0.221 759 60 0.037 761 60 0.092 780 60 0.128 83460 0.234 841 60 0.917 851 60 0.883 1064 60 0.018 1167 60 0.025 1186 600.035 1207 60 0.014 1231 60 0.131 1270 60 0.265 1274 60 0.248 1281 600.194 777 60a 0.048 789 60a 0.043 798 60a 0.004 858 60a 0.561 866 60a0.824 1206 60a 0.018 1215 60a 0.006 1227 60a 0.011 1229 60a 0.011 126460a 0.251 1289 60a 0.130 1291 60a 0.179 1296 60a 0.197 932 60b 0.008 93360b 0.034 934 60b 0.025 935 60b 0.034 936 60b 0.012 937 60b 0.096 93860b 0.091 939 60b 0.302 940 60b 0.259 941 60b 0.389 942 60b 0.135 94360b 1.045 944 60b 0.802 945 60b 0.083 509 61 0.033 653 61 0.011 895 610.000 593 62 0.010 701 62 0.008 1132 62 0.002 572 62a 0.030 634 62a0.054 1340 62a 0.001 1341 62a 0.001 1344 62a 0.010 1345 62a 0.006 982 630.010 986 64 0.005 510 65 0.068 513 65 0.009 528 65 0.049 570 65 0.030691 65 0.004 695 65 0.001 707 65 0.002 712 65 0.028 714 65 0.005 737 650.031 1058 65 0.007 1095 65 0.011 1098 65 0.031 1346 65 0.002 951 660.117 506 67 0.059 673 67 0.050 896 67 0.008 512 67a 0.050 664 67a 0.006699 67a 0.041 505 67b 0.010 657 67b 0.002 0.002 674 67b 0.003 692 67b0.005 899 67b 0.000 649 68 0.001 700 68 0.006 704 68a 0.017 705 68a0.012 574 69 0.048 631 70 0.052 632 70 0.037 1069 70 0.028 1348 70 0.0000.002 1349 70 0.005 0.006 1111 70a 0.009 1350 70a 0.001 1076 70b 0.0201355 70b 0.002 1414 70c 0.003 1415 70c 0.011 1416 70c 0.015 711 71 0.050813 71 0.499 1031 71 0.134 1032 71 1.100 1035 71 1.008 1046 71 0.0641047 71 0.471 1048 71 0.146 1029 72 0.006 1030 72 0.033 1036 72 0.0051037 72 0.022 1038 72 0.002 1039 72 0.007 1040 72 0.014 1043 72 0.0551049 72 0.050 1050 72 0.085 1051 72 0.175 1052 72 0.065 1411 72 0.0011044 72a 0.945 1045 72a 0.190 534 >76.6655 535 10.000 536 10.000540 >31.2464 725 0.293 847 5.000 867 >31.2464 870 100.000 1487 >31.24641454 >31.2464 1505 >31.2464 1455 >31.2464 1456 >31.2464 1435 20.012 15041503 >31.2464 1502 >31.2464 1461  9i 100.000

In Vivo Methods Example 4 CFA-Induced Paw Radiant Heat Hypersensitivity

Each rat was placed in a test chamber on a warm glass surface andallowed to acclimate for approximately 10 min A radiant thermal stimulus(beam of light) was then focused through the glass onto the plantarsurface of each hind paw in turn. The thermal stimulus was automaticallyshut off by a photoelectric relay when the paw was moved or when thecut-off time was reached (20 sec for radiant heat at ˜5 amps). Aninitial (baseline) response latency to the thermal stimulus was recordedfor each animal prior to the injection of complete Freund's adjuvant(CFA). 24 h following intraplantar CFA injection, the response latencyof the animal to the thermal stimulus was then re-evaluated and comparedto the animal's baseline response time. Only rats that exhibited atleast a 25% reduction in response latency (i.e., were hyperalgesic) wereincluded in further analysis. Immediately following the post-CFA latencyassessment, the indicated test compound or vehicle was administeredorally. Post-compound treatment withdrawal latencies were assessed atfixed time intervals, typically 30, 60, 120, 180, and 300 min.

The percent reversal (% R) of hypersensitivity was calculated in one oftwo different ways: 1) using group mean values or 2) using individualanimal values. More specifically:

Method 1

For all compounds, the % R of hypersensitivity was calculated using themean value for groups of animals at each time point according to thefollowing formula:

% reversal=[(group treatment response−group CFA response)/(groupbaseline response−group CFA response)]×100

Results are given for the maximum % reversal observed for each compoundat any time point tested.

Method 2.

For some compounds, the % R of hypersensitivity was calculatedseparately for each animal according to the following formula:

% reversal=[(individual treatment response−individual CFAresponse)/(individual baseline response−individual CFA response)]×100.

Results are given as a mean of the maximum % reversal values calculatedfor each individual animal.

BIOLOGICAL TABLE 4 CFA thermal hypersensitivity dose last time Method 1:Method 2: (mg/kg, no. of point peak % peak % cmpd p.o.) vehicle animals(min) reversal reversal 5 30 HPβCD 9 180 96.6 100.5 7 30 HPβCD 8 18077.8 76.2 9 30 HPβCD 8 180 75.4 77.4 39 30 HPβCD 8 180 39.1 39.7 126 10HPβCD 8 300 40.8 40.4 126 30 HPβCD 8 300 51 79.5 229 30 HPβCD 8 300 55.856.6 232 30 HPβCD 8 180 9.6 8 239 30 HPβCD 8 300 81.8 87.5 240 30 HPβCD8 300 43 44.4 250 30 HPβCD 8 300 41.7 41.9 251 30 HPβCD 8 300 35.1 38.5253 30 HPβCD 8 300 64.3 87.2 261 30 HPβCD 8 300 26.4 27.5 266 30 HPβCD 8300 50.5 56.1 314 30 HPβCD 8 180 41 41.2 316 30 HPβCD 8 180 69.3 70.8317 30 HPβCD 8 300 43 318 30 HPβCD 8 300 44.7 324 30 HPβCD 8 300 48.755.8 325 30 HPβCD 9 300 62.1 63.1 326 30 HPβCD 8 300 17.3 17.5 331 30HPβCD 8 300 14.3 333 30 HPβCD 8 300 27.7 335 30 HPβCD 8 300 108.2 135.2337 30 HPβCD 9 300 14.3 17.6 345 30 HPβCD 8 300 25 26.3 407 30 HPβCD 8300 1.6 1.4 485 30 HPβCD 8 300 34.4 32.3 487 30 HPβCD 8 300 109.2 166.5488 30 HPβCD 8 300 78 85.5 489 30 HPβCD 8 180 27.1 43.5 490 30 HPβCD 8300 18.4 19.7 509 30 HPβCD 8 300 17.8 567 30 HPβCD 8 300 63.1 571 30HPβCD 8 300 133.2 572 30 HPβCD 8 300 −5.1 650 30 HPβCD 8 300 29.9 653 30HPβCD 8 300 −10.7 657 30 HPβCD 8 300 66 662 30 HPβCD 8 300 21 24 663 30HPβCD 8 300 33.9 666 30 HPβCD 8 300 −3.1 670 30 HPβCD 8 300 20.9 674 30HPβCD 8 300 57.7 895 30 HPβCD 8 300 23.4 899 30 HPβCD 8 300 80.1 900 30HPβCD 8 300 8.5 1010 30 HPβCD 8 300 23.4 1054 30 HPβCD 8 300 27.6 107030 HPβCD 8 300 25.7 23.1 1088 30 HPβCD 8 300 35.3 1102 30 HPβCD 8 300 3845.3 1106 30 HPβCD 8 300 45 1108 30 HPβCD 8 300 84.9 99.2 1117 30 HPβCD8 300 23.2 1124 30 HPβCD 8 300 88.1 1125 30 HPβCD 8 300 64.5 90.3 113230 HPβCD 8 300 0 1139 30 HPβCD 8 300 43.8 1141 30 HPβCD 8 300 5.7 117430 HPβCD 8 300 13.6 1187 30 HPβCD 8 300 16.3 1221 30 HPβCD 8 300 44.746.7 1337 30 HPβCD 8 300 6.7 1338 30 HPβCD 8 300 86.3 1340 30 HPβCD 8300 13.1 1341 30 HPβCD 8 300 7.5 1357 30 HPβCD 8 300 51 46.1 1358 30HPβCD 8 300 25.4 1359 30 HPβCD 8 300 5.1 12.7 1360 30 HPβCD 8 300 40.540.5 1362 30 HPβCD 8 300 185.9 1363 30 HPβCD 8 300 69.7 1364 30 HPβCD 8300 17 1366 30 HPβCD 8 300 47.1

Example 5 CFA-Induced Paw Pressure Hypersensitivity

Prior to testing, rats were acclimated to the handling procedure twice aday for a period of two days. The test consisted of placing the lefthindpaw on a Teflon® (polytetrafluoroethylene) coated platform andapplying a linearly increasing mechanical force (constant rate of 12.5mmHg/s) in between the third and fourth metatarsal of the dorsum of therat's hindpaw, with a dome-tipped plinth (0.7 mm in radius), using ananalgesy-meter (Stoelting, Chicago, Ill.), also known as aRandall-Selitto apparatus. The endpoint was automatically reached uponhindpaw withdrawal, and the terminal force was noted (in grams). Aninitial (baseline) response threshold to the mechanical stimulus wasrecorded for each animal prior to the injection of complete Freund'sadjuvant (CFA). Forty hr following intraplantar CFA injection, theresponse threshold of the animal to the mechanical stimulus wasre-evaluated and compared to the animal's baseline response threshold. Aresponse was defined as a withdrawal of the hindpaw, a struggling toremove the hindpaw or vocalization. Only rats that exhibited at least a25% reduction in response threshold (i.e., hyperalgesia) were includedin further analysis. Immediately following the post-CFA thresholdassessment, rats were administered the indicated test compound orvehicle. Post-treatment withdrawal thresholds were assessed at 1 h. Pawwithdrawal thresholds were converted to percent reversal ofhypersensitivity according to the following formula:

% reversal=[(post treatment response-predose response)/(baselineresponse-predose response)]×100.

BIOLOGICAL TABLE 5 CFA induced paw pressure hypersensitivity route oftime percent cmpd N dose administration vehicle (h) reversal 487 8 30s.c. HPβCD 1 61.8 1362 10 30 s.c. HPβCD 1 56.7

Example 6 Chronic Constriction Injury (CCI)-Induced Model of NeuropathicPain—Cold Acetone-Hypersensitivity Test

Male Sprague-Dawley rats (225-450 g) were used to evaluate the abilityof selected compounds to reverse CCI-induced cold hypersensitivity. Fourloose ligatures of 4-0 chromic gut were surgically placed around theleft sciatic nerve under inhalation anesthesia as described by Bennettet al. (Bennett G J, Xie Y K. Pain 1988, 33(1): 87-107). Fourteen to 35days following CCI surgery, subjects were placed in elevated observationchambers containing wire mesh floors, and five applications of acetone(0.05 mL/application separated by about 5 min) were spritzed onto theplantar surface of the paw using a multidose syringe. An abruptwithdrawal or lifting of the paw was considered a positive response. Thenumber of positive responses was recorded for each rat over the fivetrials. Following baseline withdrawal determinations, compounds wereadministered in the indicated vehicle, by the indicated route (see Table6). The number of withdrawals was re-determined 1 to 4 h after compoundadministration. Results are presented as a percent inhibition of shakes,which was calculated for each subject as [1−(test compoundwithdrawals/pre-test withdrawals)]×100 and then averaged by treatment.

BIOLOGICAL TABLE 6 CCI induced cold sensitivity dose route of last timepeak percent cpd N (mg/kg) administration vehicle point (h) inhibition 59 30 p.o. HPβCD 4 26.7 335 9 30 p.o. HPβCD 4 100 487 9 30 p.o. HPβCD 4100 1362 6 3 p.o. HPβCD 4 70.0

Example 7 Spinal Nerve Ligation (SNL) Model of Neuropathic Pain—TactileAllodynia Test

For lumbar 5 (L₅) spinal nerve ligation (SNL) studies, anesthesia wasinduced and maintained on isoflurane inhalation. Fur was clipped overthe dorsal pelvic area, and a 2-cm skin incision was made just left ofmidline over the dorsal aspect of the L₄-S₂ spinal segments, followed byseparation of the paraspinal muscles from spinous processes. Thetransverse process of L₆ was then carefully removed, and the L₅ spinalnerve was identified. The left L₅ spinal nerve was then ligated tightlywith 6-0 silk thread, the muscle was sutured with 4-0 vicryl, and theskin was closed with wound clips. Following surgery, s.c. saline (5 mL)was administered.

Behavioral testing was performed four weeks post-ligation. Followingbaseline von Frey determinations to verify the presence of mechanicalallodynia, L₅ SNL rats were orally administered the indicated vehicle ordrug. Tactile allodynia was quantified at 30, 60, 100, 180 and 300 minpost-dosing by recording the force at which the paw ipsilateral to thenerve ligation was withdrawn from the application of a series ofcalibrated von Frey filaments (0.4, 0.6, 1.0, 2.0, 4, 6, 8 and 15 g;Stoelting; Wood Dale, Ill.). Beginning at an intermediate stiffness (2.0g), filaments were applied to the mid-plantar hind paw for approximately5 seconds. to determine the response threshold, a brisk paw withdrawalled to the presentation of the next lighter stimulus, whereas a lack ofa withdrawal response led to the presentation of the next strongerstimulus. A total of four responses after the first threshold detectionwere collected. The 50% withdrawal thresholds were interpolated by themethod of Dixon, Efficient analysis of experimental observations. Annu.Rev. Pharmacol. Toxicol. 20:441-462 (1980) as modified by Chaplan et.al., Quantitative assessment of tactile allodynia in the rat paw, J.Neurosci. Methods. 53(1):55-63 (1994) and when response thresholds fellabove or below the range of detection, respective values of 15.0 or 0.25g were assigned. Threshold data from von Frey filament testing werereported as withdrawal threshold in grams. Data were normalized andresults are presented as % MPE (maximum possible effect) of the drugcalculated according to the following formula:

${\% \mspace{14mu} {MPE}} = {\frac{{x\mspace{14mu} g\text{/}{force}} - {{baseline}\mspace{14mu} g\text{/}{force}}}{{15\mspace{14mu} g\text{/}{force}} - {{baseline}\mspace{14mu} g\text{/}{force}}}100}$

BIOLOGICAL TABLE 7 Spinal nerve ligation - tactile allodynia dose routeof last time peak % cmpd N (mg/kg) administration vehicle point (h) MPE335 6 30 p.o. HPβCD 4 50.1 487 6 30 p.o. HPβCD 4 61.2 1362 6 30 p.o.HPβCD 4 84.3

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1.-18. (canceled)
 19. A compound of Formula (I)

selected from the group consisting of: a compound wherein Y is phenyl, Zis 4-(3-trifluoromethylphenyl)phenyl, and s is 0; a compound wherein Yis penta-deuterated phenyl, Z is 4-(3-trifluoromethylphenyl)phenyl, ands is 0; a compound wherein Y is phenyl, Z is4-(2-trifluoromethoxyphenyl)phenyl, and is 0; a compound wherein Y isphenyl, Z is 4-(3-dimethylaminosulfonylamino-phenyl)phenyl, and s is 0;a compound wherein Y is phenyl, Z is1-(4-trifluoromethylphenyl)-1H-indol-5-yl, and s is 0; a compoundwherein Y is phenyl, Z is 4-(2-trifluoromethylphenyl)phenyl, and s is 0;a compound wherein Y is phenyl, Z is4-(4-chloro-3-trifluoromethylphenyl)phenyl, and s is 0; a compoundwherein Y is phenyl, Z is 1-phenyl-indol-5-yl, and s is 0; a compoundwherein Y is phenyl, Z is 3-methyl-4-(3-trifluoromethylphenyl)phenyl,and s is 0; a compound wherein Y is phenyl, Z is2-fluoro-4-(3-trifluoromethylphenyl)phenyl, and s is 0; a compoundwherein Y is phenyl, Z is 3-methoxy-4-(3-trifluoromethylphenyl)phenyl,and s is 0; a compound wherein Y is phenyl, Z is2-chloro-4-(3-trifluoromethylphenyl)phenyl, and s is 0; a compoundwherein Y is phenyl, Z is 2-methyl-4-(3-chloro-4-fluorophenyl)phenyl,and s is 0; a compound wherein Y is phenyl, Z is3-methyl-4-(3-chloro-4-fluorophenyl)phenyl, and s is 0; a compoundwherein Y is phenyl, Z is3-methyl-4-(4-chloro-3-trifluoromethylphenyl)phenyl, and s is 0; acompound wherein Y is phenyl, Z is3-methoxy-4-(3-chloro-4-fluorophenyl)phenyl, and s is 0; a compoundwherein Y is phenyl, Z is3-methoxy-4-(4-chloro-3-trifluoromethylphenyl)phenyl, and s is 0; acompound wherein Y is phenyl, Z is2-chloro-4-(3-chloro-4-fluorophenyl)phenyl, and s is 0; a compoundwherein Y is phenyl, 3-chloro-6-phenyl-benzothien-2-yl, and s is 0; acompound wherein Y is phenyl, Z is1-(4-cyano-3-methylphenyl)-indol-5-yl, and s is 0; a compound wherein Yis phenyl, Z is 1-(4-fluorophenyl)-indol-5-yl, and s is 0; a compoundwherein Y is penta-deuterated phenyl, Z is1-(4-fluorophenyl)-indol-5-yl, and s is 0; a compound wherein Y isphenyl, Z is 1-(3,4,5-trifluorophenyl)-indol-5-yl, and s is 0; acompound wherein Y is phenyl, Z is 3-methyl-5-phenyl-benzo[b]thien-2-yl,and s is 0; a compound wherein Y is phenyl, Z is1-(3,4-difluorophenyl)-indol-5-yl, and s is 0; a compound wherein Y isphenyl, Z is 3-(3-trifluoromethylphenyl)-1H-indol-6-yl, and s is 0; acompound wherein Y is phenyl, Z is 1-phenyl-1H-indazol-5-yl, and s is 0;a compound wherein Y is phenyl, Z is 2-chloro-4-phenyl-phenyl, and s is0; a compound wherein Y is phenyl, Z is 3-methyl-4-phenyl-phenyl, and sis 0; a compound wherein Y is phenyl, Z is 2-fluoro-4-phenyl-phenyl, ands is 0; a compound wherein Y is phenyl, Z is 3-methoxy-4-phenyl-phenyl,and s is 0; or a pharmaceutically acceptable salt form thereof.
 20. Apharmaceutical composition comprising a compound of claim 19 and atleast one of a pharmaceutically acceptable carrier, a pharmaceuticallyacceptable excipient and a pharmaceutically acceptable diluent.
 21. Apharmaceutical composition of claim 20, wherein the composition is asolid oral dosage form.
 22. A pharmaceutical composition of claim 20,wherein the composition is a syrup, an elixir or a suspension.